[Federal Register Volume 63, Number 16 (Monday, January 26, 1998)]
[Notices]
[Pages 3750-3752]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-1664]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 97D-0528]
Draft ``Guidance for Industry: Efficacy Studies to Support
Marketing of Fibrin Sealant Products Manufactured for Commercial Use''
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is announcing the
availability of a draft document entitled ``Guidance for Industry:
Efficacy Studies to Support Marketing of Fibrin Sealant Products
Manufactured for Commercial Use.'' After reviewing recent experience
with fibrin sealant products in clinical studies conducted under
Investigational New Drug (IND) regulations, the agency is proposing to
accept applications for licensure of fibrin sealant products based on
evidence from pivotal studies in which the primary endpoint is
hemostasis effectiveness. As in the past, other endpoints such as wound
healing or tissue sealing may serve as primary endpoints for pivotal
studies, depending on the nature of the indications sought. This draft
document will provide guidance to manufacturers of fibrin sealant
products for the design of clinical trials intended to support
licensure.
DATES: Written comments may be submitted at any time, however, comments
should be submitted by April 27, 1998, to ensure their adequate
consideration in preparation of the final document.
ADDRESSES: Submit written requests for single copies of the draft
guidance document ``Guidance for Industry: Efficacy Studies to Support
Marketing of Fibrin Sealant Products Manufactured for Commercial Use''
to the Office of Communication, Training, and Manufacturers Assistance
(HFM-40), Center for Biologics Evaluation and Research (CBER), Food and
Drug Administration, 1401 Rockville Pike, Rockville, MD 20852-1448.
Send one self-addressed adhesive label to assist that office in
processing your requests. The draft guidance document may also be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. Submit written comments on
the draft guidance document to the Dockets Management Branch (HFA-305),
Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville,
MD 20857.
FOR FURTHER INFORMATION CONTACT: Paula S. McKeever, Center for
Biologics Evaluation and Research (HFM-17), Food and Drug
Administration, 1401 Rockville Pike, Rockville, MD 20852-1448, 301-827-
6210.
SUPPLEMENTARY INFORMATION:
I. Background
FDA is announcing the availability of a draft document entitled
``Efficacy Studies to Support Marketing of Fibrin Sealant Products
Manufactured for Commercial Use.'' This draft guidance document
represents the agency's current thinking with regard to information on
the efficacy studies to support marketing of licensure of fibrin
sealant products manufactured for commercial use. It does not create or
confer any rights for or on any person and does not operate to bind FDA
or the public. An alternative approach may be used if such approach
satisfies the requirements of the applicable statute, regulations, or
both. As with other guidance documents, FDA does not intend this draft
document to be all-inclusive and cautions that not all information may
be applicable to all situations. The draft guidance document is
intended to provide information and does not set forth requirements.
II. Comments
This draft document is being distributed for comment purposes only,
and is not intended for implementation as general guidance at this
time. Interested persons may submit to the Dockets Management Branch
(address above) written comments on the draft guidance document.
Written comments may be submitted at any time, however, comments should
be submitted by April 27, 1998, to ensure adequate consideration in
preparation of the final document. Two copies of any comment are to be
submitted, except individuals may submit one copy. Comments and request
for copies should be identified with the docket number found in the
brackets in the heading of this document. A copy of the draft guidance
document and received comments are available for public examination in
the Dockets Management Branch between 9 a.m. and 4 p.m., Monday through
Friday.
III. Electronic Access
Persons with access to the internet may obtain the draft document
using the World Wide Web (WWW). For WWW access connect to CBER at
``http://www.fda.gov/cber/guidelines.htm''.
Dated: January 13, 1998.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
The text of the draft guidance is set forth below:
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Draft-Not for Implementation
Guidance for Industry \1\: Efficacy Studies to Support Marketing of
Fibrin Sealant Products Manufactured for Commercial Use
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\1\ This draft guidance document represents the FDA's current
thinking on efficacy studies to support marketing of fibrin sealant
products manufactured for commercial use. It does not create or
confer any rights for or on any person and does not operate to bind
FDA or the public. An alternative approach may be used if such
approach satisfies the requirements fo the applicable statute,
regulations, or both. For additional copies of this guidance,
contact the Office of Communication, Training and Manufacturers
Assistance, HFM-40, Center for Biologics Evaluation and Research,
Food and Drug Administration, 1401 Rockville Pike, Rockville, MD
20852-1448. Send one self-addressed adhesive label to assist that
office in processing your requests. The document 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. Persons with
access to the INTERNET may obtain the document using the World Wide
Web (WWW) by connecting to CBER at ``http//www.fda.gov/cber/
guidelines.htm''.
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I. Introduction
This document pertains to commercially-produced fibrin sealants
composed of purified, virus-inactivated/removed human fibrinogen and
human or bovine thrombin, with or without added components such as
virus-inactivated/removed human factor XIII and/or aprotinin. Such
products are currently available in Europe and Canada as hemostasis
agents. Although manufacturers and clinicians in the United States
have been actively engaged in the development and testing of fibrin
sealants, no fibrin sealant product has been licensed in this
country. This document outlines the agency's current position with
regard to clinical data used to support licensure of safe and
effective commercially-produced fibrin sealants in the United
States.
II. Background
As early as 1909, surgeons were reporting the hemostatic
properties of fibrin powder used in the operative field. In the
1940s, combinations of fibrinogen and thrombin were first utilized.
The development of Cohn fractionation in the 1940s, and a method for
cryoprecipitation of fibrinogen in the 1960s, led to the development
of fibrin sealants in the 1970s. However, fibrinogen concentrates
were found to transmit hepatitis and thus all U.S. licenses for
Fibrinogen (Human) were revoked on December 7, 1977. Since that
time, a number of manufacturers have been evaluating a new
generation of virus-inactivated/removed fibrin sealants.
In 1994, the FDA co-sponsored a conference on the
characteristics and clinical uses of fibrin sealants, held at the
Uniformed Services University of the Health Sciences, Bethesda,
Maryland (summarized in Transfusion 35:783-790, 1995). A number of
academic investigators presented data from clinical trials in which
fibrin sealants either reduced blood loss or reduced the time to
achieve hemostasis. However, based on the available data, FDA
representatives were of the opinion that a direct clinical benefit
to patients treated with fibrin sealant should be demonstrated in a
well-controlled clinical trial to support product licensure for a
narrow indication.
Despite FDA's requests for well-controlled trials with patient
outcomes as endpoints, many clinicians have been reluctant to
conduct placebo-controlled trials in settings where they view the
standard of care to be the use of fibrin sealant prepared on site
from commercial bovine thrombin and various sources of fibrinogen.
These clinicians consider the use of locally-prepared fibrin sealant
to be of such benefit in controlling bleeding in confined or nearly
inaccessible areas that a placebo-controlled trial would put the
control patients at significant and unnecessary risk. However,
locally-prepared fibrin sealants are not standardized or consistent,
and the available sources of fibrinogen are not treated to
inactivate or remove viruses.
III. Guidance
Based on clinical trial experience since 1994, FDA's Center for
Biologics Evaluation and Research (CBER) proposes to consider, for
licensure of commercially-produced fibrin sealants, data from
pivotal studies in which the primary endpoint is hemostasis
effectiveness. This review standard is similar to that used by the
Center for Devices and Radiological Health, in clearing a number of
commercial medical devices on the basis of clinical studies in which
the primary endpoint was control of hemostasis within a specific
time in a variety of clinical settings. CBER proposes that time to
hemostasis could also serve as a primary endpoint for pivotal
studies of fibrin sealants.
As in the past, CBER also encourages manufacturers to conduct
well-controlled clinical trials using a variety of other endpoints,
including blood loss, transfusion requirements, tissue sealing, and
wound healing. Endpoints for such trials will be reviewed on a case-
by-case basis. Manufacturers who demonstrate the safety and efficacy
of their fibrin sealant preparations for specific indications may,
upon FDA licensure, label and promote their products for these
indications. FDA licensure for a given indication will denote that
the specific formulation of fibrin sealant is safe and effective for
that specific indication.
For fibrin sealant products containing multiple biologic
components, the contribution of each component may be demonstrated
in a non-clinical setting appropriate to the indication(s) sought,
although the overall efficacy of multiple-component fibrin sealant
products should be demonstrated in clinical trials. Proposals to
utilize in vitro and/or animal studies to support the inclusion of
multiple biologic components into a fibrin sealant product should be
discussed with CBER.
The following points are proposed for review of pivotal clinical
trials of fibrin sealant products:
1) Fibrin sealant products should be tested in settings and under
conditions where they would normally be expected to be used in clinical
practice.
2) Fibrin sealant products may be tested against a placebo, a cleared
hemostatic device, or other control, as appropriate.
3) Efficacy of fibrin sealant products may be tested by using either
hemostasis endpoints or other measures of clinical benefit, depending
on the indications sought.
IV. Comments
The agency will review all submitted comments and consider them
in the preparation of any final guidance document. Two copies of any
comment 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.
[FR Doc. 98-1664 Filed 1-23-98; 8:45 am]
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