[Federal Register Volume 60, Number 137 (Tuesday, July 18, 1995)]
[Notices]
[Pages 36808-36811]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-17535]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
[Docket No. 95N-0200]


Public Hearing: Products Comprised of Living Autologous Cells 
Manipulated ex vivo and Intended for Implantation for Structural Repair 
or Reconstruction

Agency: Food and Drug Administration, HHS.

Action: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing a public 
hearing to discuss the regulation of products that are comprised of 
living autologous cells manipulated ex vivo and intended for 
implantation for structural repair or reconstruction of the source 
tissue or other tissue, including products used for cosmetic 
reconstruction and augmentation. The products to be discussed at this 
hearing are described in further detail in this document.
    In view of the emergence of new autologous cell products and the 
potential enhancement to the public health, the purpose of the hearing 
is to solicit information and views from interested persons, including 
scientists, clinical investigators, professional groups, trade groups, 
commercial enterprises, and consumers, on the issues and concerns 
relating to regulation of such products.
    Preregistration by written notice is advised to ensure 
participation. The procedures governing the hearing are found in 21 CFR 
part 15.

DATES: Submit written notices of participation by October 26, 1995. The 
public hearing is scheduled for November 16 and 17, 1995, from 9 a.m. 
to 5 p.m. Written comments will be accepted until February 16, 1996.

ADDRESSES: The public hearing will be held at the Gaithersburg Hilton, 
620 Perry Pkwy., Gaithersburg, MD 20877, 301-977-8900. Submit written 
notices of participation and comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr., 
Rockville, MD 20857. Two copies of any comments are to 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 may be seen in the Dockets Management Branch 
(address above) between 9 a.m. and 4 p.m., Monday through Friday. 
Transcripts of the hearing also will be available for review at the 
Dockets Management Branch.

FOR FURTHER INFORMATION CONTACT: Andrea E. Chamblee, Office of the 
Commissioner (HF-7), Food and Drug Administration, 5600 Fishers Lane, 
Rockville, MD 20857, 301-443-1306.

SUPPLEMENTARY INFORMATION:

I. Background

    Over the last several years, FDA has worked to clarify its approach 
to the regulation of products that are comprised in whole or in part of 
living cellular materials. The agency's approach has been embodied in 
several recent policy statements. The agency's statement on somatic 
cell therapy was published in a notice in the Federal Register of 
October 14, 1993 (58 FR 53248). The agency's position on banked human 
tissue was outlined in an interim rule published in the Federal 
Register on December 14, 1993 (58 FR 65514).
    As noted, the agency described its policies for the regulation of 
somatic cell therapies in an October 1993 notice. The somatic cell 
statement defined somatic cell therapy products as autologous (i.e., 
self), allogeneic (i.e., intra-species), or xenogeneic (i.e., inter-
species) cells that have been propagated, expanded, selected, 
pharmacologically treated, or otherwise altered in biological 
characteristics ex vivo (i.e., outside the body) to be administered to 
humans and applicable to the prevention, treatment, cure, diagnosis, or 
mitigation of disease or injuries. FDA defined ``manipulation'' as the 
ex vivo propagation, expansion, selection, or pharmacological treatment 
of cells, or other alteration of their biological characteristics.
    The statement outlined the regulatory controls over somatic cell 
therapy products, and explained that the degree of regulatory control 
reflected the extent and intent of cell processing ex vivo. Thus, in 
accordance with the statement, cells manipulated in a way that changed 
the biological characteristics of the cell population would be subject 
to product licensure as final biological products. The statement also 
made clear that such products would be subject to all other pertinent 
regulatory requirements, including provisions governing drug listing 
and registration, and rules governing misbranding and adulteration.
    In contrast, the October 1993 notice on somatic cell products 
stated that applications for premarket approval were not presently 
required for certain other cellular products, including minimally 
manipulated or purged bone marrow, and certain minimally processed cell 
transplants.
    The statement also indicated that the field of somatic cell therapy 
was dynamic and rapidly expanding, and stated that, ``[a]s scientific 
knowledge in the area of somatic cell therapy continues to accumulate 
and evolve, the agency's approach may also evolve'' (58 FR 53248). The 
agency also acknowledged the need to reconsider periodically its 
approach to these evolving products in an article by FDA's Commissioner 
David Kessler, entitled ``Regulation of Somatic-Cell Therapy and Gene 
Therapy by the Food and Drug Administration'' that published in the New 
England Journal of Medicine on October 14, 1993. That article observed 
that, ``[a]s these novel therapeutic applications are explored and 
knowledge about risks and benefits accumulates, the FDA's regulatory 
approach may be modified.''
    In the Federal Register of December 14, 1993 (58 FR 65514), FDA 
established certain requirements for banked human tissue intended for 
transplantation. Banked human tissue products are described in the 
interim final rule as 

[[Page 36809]]
any tissue derived from a human body which: (1) Is intended for 
administration to another human for the diagnosis, cure, mitigation 
treatment, or prevention of any condition or disease; (2) is recovered, 
processed, stored, or distributed by methods not intended to change 
tissue function or characteristics; (3) is not currently regulated as a 
human drug, biological product, or medical device; (4) excludes kidney, 
liver, heart, lung, pancreas, or any other vascularized human organ; 
and (5) excludes semen or other reproductive human tissues, human milk, 
and bone marrow. The interim final rule specifically excluded 
autologous products.
    Thus, the agency's policies on somatic cell therapy, gene therapy, 
and banked human tissue for transplantation contemplated that changes 
in the products, and greater understanding of the benefits and risks of 
new products, might lead to modifications in the agency's regulatory 
approach.

II. Development of Autologous Cellular Products for Structural 
Repair and Reconstruction

    The agency is aware of an increasing number of reports in the 
scientific literature of the clinical use of autologous cells 
manipulated ex vivo that are intended for implantation. One recent 
article reported a Swedish study of autologous chondrocyte 
transplantation in 23 patients with deep cartilage defects in the knee 
(Ref. 1). Another article reported that mesenchymal cells harvested for 
expansion ex vivo and implanted in experimental animals can 
differentiate into bone, muscle, cartilage, and other mesenchymal 
tissues (Ref. 2). In recent years, other articles have described the 
use of autologous skin cells for burns and wounds (Refs. 3 and 4), and 
the use of cultured melanocytes for vitiligo (Refs. 5 and 6). Still 
other articles reported the ex vivo culturing of autologous skin to 
treat burns and vitiligo (Refs. 7 and 8).

References

    1. Brittberg, M. et al., ``Treatment of Deep Cartilage Defects 
in the Knee With Autologous Chondrocyte Transplantation,'' New 
England Journal of Medicine, 331:889-895.
    2. Mesenchymal Stem Cells in Bone Development, Bone Repair, and 
Skeletal Regeneration Therapy, Journal of Cellular Biochemistry 
56:283-294, 1994.
    3. Navsaria, H. A., S. R. Myers, I. M. Leigh, and I. A. McKay, 
``Culturing Skin In Vitro for Wound Therapy,'' Trends in 
Biotechnology, 13(3): 91-100, March 1995.
    4. Malakhov, S. F., B. A. Paramonov, A. V. Vasiliev, and V. V. 
Terskikh, ``Preliminary Report of the Clinical Use of Cultured 
Allogeneic Keratinocytes,'' Burns, 20(5):463-466, October 1994.
    5. Olsson, M. J., G. Moellmann, A. B. Lerner, and L. Juhlin, 
``Vitiligo: Repigmentation With Cultured Melanocytes After 
Cryostorage,'' Acta Dermato-Venereologica, 74(3):226-228, May 1994.
    6. Zachariae, H., C. Zachariae, B. Deleuran, and P. Kristensen, 
``Autotransplantation in Vitiligo: Treatment With Epidermal 
Grafts,'' Acta Dermato-Venereologica, 73(1):46-48, February 1993.
    7. Navsaria, H. A., S. R. Myers, I. M. Leigh, and I. A. McKay, 
``Culturing Skin In Vitro for Wound Therapy,'' Trends in 
Biotechnology, 13(3):91-100, March 1995.
    8. Tissue Engineering and the Human Body Shop: Encapsulated-cell 
Transplants Enter the Clinic, Journal of NIH Research, 47-51, 1995.
    In addition to these reports from the scientific literature, the 
agency has received an increasing number of inquiries from companies 
about the regulation of autologous products intended for implantation. 
The inquiries have been made for a variety of products intended to 
replace or repair tissue that is nonfunctioning or diseased, including 
cosmetic augmentation, dermal wound healing, and cartilage replacement 
for damaged knees. The products may have characteristics of drugs, 
biological products, and devices, and some may be combination products. 
(See 21 CFR part 3.)
    These reports in the literature and inquiries to the agency may 
reflect changes in what is understood about the science of autologous 
cell transplantation. The reports also signal a significant evolution 
in the nature of the products. As technologies are developing, these 
products increasingly are being commercialized and made available on a 
larger scale to patients.

III. Purpose and Scope of the Hearing

    The promise of products that use autologous cells for implantation 
is great, and the demand for them is expected to be correspondingly 
high. Successful development and marketing of these products may be 
slowed by questions about the scope of regulatory requirements. In 
light of the potential public health significance of the new products, 
the growth of a commercial industry, and the need to develop an 
appropriate regulatory framework for products comprised of autologous 
cells for implantation for repair or reconstruction, the agency has 
decided to hold a public hearing to solicit information on the nature 
and diversity of these products, and comments on the formulation and 
implementation of appropriate regulatory requirements.
    The hearing will be limited to discussion of autologous cells 
manipulated ex vivo, and intended for implantation for structural 
repair or reconstruction of the source tissue or other tissue, 
including products intended for cosmetic reconstruction and 
augmentation. Examples of these products include cartilage, fat, and 
skin cells, removed, manipulated ex vivo, and implanted in the patient, 
either at the site where the cellular material was removed or at 
another site. These products will be referred to hereinafter as 
``manipulated autologous structural cells (MAS cells).''
    Allogeneic and xenogeneic products are beyond the scope of the 
hearing. In addition, the hearing will not consider products intended 
for nonstructural purposes, including, for example, autologous 
pancreatic cells to produce insulin following total pancreatectomy, 
autologous stem cells for functional replacement of muscle, and 
autologous lymphocytes activated to induce immune function.
    Gene therapy products also are beyond the scope of this hearing. 
Gene therapy products are products containing genetic material 
administered to modify or manipulate the expression of genetic material 
or to alter the biological properties of living cells.

IV. Issues for Discussion

    The agency recognizes the importance of facilitating the 
introduction of useful new technologies while minimizing regulatory 
burdens. The agency notes that there are a variety of products covered 
by this hearing (see section III. of this document) and that different 
regulatory approaches may be appropriate for different types of MAS 
cells. Participants should address appropriate distinctions among MAS 
cells. To assist in the development of an appropriate regulatory 
strategy, the agency invites information and comments on the following:
    (a) What are the public health benefits of products in this group? 
What alternative therapies exist?
    (b) What are the public health risks of products in this group? 
What are the risks of contamination associated with the ex vivo 
processing of the cellular material? What other potential risks exist?
    (c) Some of the MAS cells may have characteristics of biological 
products, drugs, or devices. What are the mechanism(s) of action of 
these products?
    (d) The 1993 interim final rule for banked human tissue did not 
require premarket review and approval or provide for FDA oversight of 
tissue as regulated drugs, devices, or biological 

[[Page 36810]]
products. In contrast, many somatic cell products are subject to 
premarket review and approval and to all other pertinent requirements, 
including provisions governing misbranding and adulteration. The agency 
is interested in information and views on the relative strengths and 
weaknesses of these approaches as they relate to the regulation of MAS 
cells. In particular, the agency is interested in the following:
    (1) What are the advantages and disadvantages of an approach that 
would require premarket product approval?
    (2) If premarket approval is not required, what would be the 
advantages and disadvantages of an approach that required licensing of 
each establishment involved in the processing of the material?
    (3) If premarket product approval is required, what safety and 
efficacy information should the agency seek in a premarket submission? 
What issues are important in clinical trial design (e.g., efficacy 
measurements, endpoints)?
    (4) What role should institutional review boards or other third 
party review organizations play in the oversight of these products?
    (e) Autologous cells manipulated ex vivo for implantation for 
structural repair or reconstruction may involve intraoperative 
procedures to remove the cellular material from the patient, shipment 
of the cellular material to a distant site, processing of the material 
at that site, and the return of the processed material to the physician 
for implantation. In light of these practices, the agency seeks comment 
on the need for the following:
    (1) Recordkeeping, to enable audits, tracking, or recall, if 
necessary;
    (2) Precautions to help prevent errors and accidents, such as 
wrong-donor infusion, or potential infectious disease transmission;
    (3) Process controls and validation, to help ensure the 
appropriate characterization of the product before, during and after 
processing;
    (4) Labeling, to help ensure that users are adequately informed 
of uses and risks associated with the product;
    (5) Current good manufacturing practices (CGMP's), to help 
ensure the consistency and control of the process and product;
    (f) What amount of time should be allowed for compliance after 
adoption of new regulatory frameworks? Are there widely-practiced 
procedures, e.g., recordkeeping or other GMP's, that could be 
implemented sooner than others?

V. Current Regulatory Status of Pending and Approved Applications

    This notice is not intended to affect the status of any approved or 
pending investigational or marketing application.
    Pending the hearing and its outcome, FDA does not at this time 
intend to actively regulate products comprised of human living 
autologous cells manipulated ex vivo and intended for implantation for 
structural repair or reconstruction.
    The agency recommends that any facility that currently distributes 
or plans to distribute such products pending the outcome of this 
hearing use appropriate process controls and validation and adhere to 
current good manufacturing practices. Informed consent from the patient 
should be obtained, and labeling should be truthful and not misleading.
    In addition, recordkeeping and tracking should be performed to 
facilitate the distribution of any appropriate information, and recall 
if indicated. To guard against transmission of infectious disease, the 
facilities should take precautions to prevent errors and accidents such 
as wrong-donor infusion.

VI. Outcome of the Hearing

    After the hearing, FDA will consider the information presented at 
the hearing, all written comments submitted to the docket, and all 
other relevant information in determining the appropriate regulation of 
these products. As the agency has indicated, FDA will provide 
appropriate time for compliance with any regulatory requirements.

VII. Notice of Hearing Under 21 CFR Part 15

    For the reasons stated above, the Commissioner of Food and Drugs is 
announcing that a public hearing will be held in accordance with 21 CFR 
part 15. The purpose of hearing is to solicit information and views, 
under Sec. 15.1(a), from interested persons on the public health issues 
and concerns relating to regulation of products that are comprised of 
living autologous cells manipulated ex vivo and intended for 
implantation for structural repair or reconstruction, including repair 
or reconstruction of the source tissue.
    Every effort will be made to accommodate each person who wants to 
participate in the public hearing. However, those who want to ensure 
participation in the hearing are encouraged to submit: (1) A written 
notice of participation containing the name, address, phone number, 
facsimile number, affiliation (if any), topic of the presentation, and 
approximate amount of time requested for the presentation; and (2) a 
brief description or outline of their presentation. The information 
should be submitted to the Dockets Management Branch (address above) by 
close of business on the date specified above. Interested persons 
attending the public hearing who did not request in advance an 
opportunity to make a presentation will have an opportunity to be heard 
as time permits and at the discretion of the presiding officer.
    After reviewing the notices of participation and accompanying 
information, FDA will schedule each appearance and notify each 
participant by letter, telephone, or facsimile, with the amount of time 
assigned to each person and the approximate time his or her 
presentation is scheduled to begin. A hearing schedule will be 
available at the hearing and will be filed with the Dockets Management 
Branch (address above).
    In order to enable all interested persons to submit data, 
information, and views on this subject, the administrative record of 
the hearing will remain open until February 16, 1996. Any person may 
submit written comments to the Dockets Management Branch (address 
above) no later than February 16, 1996. The agency will consider these 
comments in formulating its conclusions. In formulating the appropriate 
regulatory framework for products involving MAS cells, the agency may 
also consider information that cannot be made public by the agency, 
e.g., confidential commercial information. The agency does not intend 
to respond to or summarize the comments received.
    The presiding officer will be the Chief Mediator and Ombudsman. The 
presiding officer will be accompanied by a panel of Public Health 
Service employees with relevant expertise.
    Under Sec. 15.30, the hearing is informal, and the rules of 
evidence do not apply. No participant may interrupt the presentation of 
another participant. Only the presiding officer or members of the panel 
may question any person during or at the conclusion of the 
presentations.
    Public hearings, including hearings under part 15, are subject to 
FDA's guideline on the policy and procedures for electronic media 
coverage of FDA's public administrative proceedings (21 CFR part 10, 
subpart C). Under Sec. 10.205, representatives of electronic media may 
be permitted, subject to certain limitations, to videotape, film, or 
otherwise record FDA's public administrative proceedings, including 
presentations by participants. The hearing will be transcribed as 
stipulated in Sec. 15.30(b). Orders for copies of the transcript can be 
placed at the meeting, or through the Dockets Management Branch 
(address above).

[[Page 36811]]

    Any handicapped persons requiring special accommodations in order 
to attend the hearing should inform the contact person listed in order 
for FDA to be prepared to meet those needs.
    To the extent that the conditions for the hearing as described in 
this notice, conflict with any provisions set out in part 15, this 
notice acts as a waiver of those provisions as specified in 
Sec. 15.30(h)

    Dated: July 10, 1995.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 95-17535 Filed 7-17-95; 8:45 am]
BILLING CODE 4160-01-F