[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ADDRESSES: Submit written requests for single copies of the draft 
guidance document ``Guidance for Industry: Efficacy Studies to Support 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 The draft guidance document may also be 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the draft guidance document to the Dockets Management Branch (HFA-305), 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 ``<a href="http//www.fda.gov/cber/
guidelines.htm">http//www.fda.gov/cber/
guidelines.htm</a>''.
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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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