Efficacy Studies to Support Marketing of Fibrin Sealant Products Manufactured for Commercial Use: Guidance for Industry

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Guidance for Industry
Efficacy Studies to Support Marketing
of Fibrin Sealant Products
Manufactured for Commercial Use
Additional copies are available from:
Office of Communication, Training and
Manufacturers Assistance (HFM-40)
1401 Rockville Pike
Rockville, MD 20852-1448
(Tel) 301-827-1800
or 1-800-835-4709
(Internet) http://www.fda.gov/cber/guidelines.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research (CBER)
May 1999

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TABLE OF CONTENTS
[Note: page numbering may vary for documents distributed electronically.]
I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
II. BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
III. GUIDANCE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

1 This 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 of the applicable statute, regulations, or both.
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Guidance for Industry1:
Efficacy Studies to Support Marketing of Fibrin Sealant
Products Manufactured For Commercial Use
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. A
number of 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, only one 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.
In the Federal Register of January 26, 1998 (63 FR 3750), the Food and Drug
Administration (FDA) announced the availability of a draft guidance for industry entitled
“Efficacy Studies to Support Marketing of Fibrin Sealant Products Manufactured for Commercial
Use.” In response to a 90 day comment period, only one comment was received. The comment
expressed concern that the wording of the draft guidance document was too restrictive with
regard to the term “specific indications”. The comment suggested that the FDA would approve
fibrin sealants only for the specific indications that were studied in the clinical trials. The comment
stated that the guidance document should recognize the use of data from representative surgical
procedures in support of a range of indications, such as arterial-venous access procedures
representing vascular surgical procedures. The FDA agrees with this recommendation and has
revised this guidance document accordingly in section III. Guidance.
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

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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 clinical 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) intends 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 devices as adjuncts to hemostasis 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
intends 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. The indication may be a group of surgical
procedures if the clinical trial data are considered to be representative of surgeries of that type.
Further, manufacturers who demonstrate the safety and efficacy of their fibrin sealant preparations
in a variety of clinical settings may, upon FDA licensure, label and promote their products as
general adjuncts to hemostasis. The number and types of procedures required to support a broad
labeling claim should be discussed with the agency.
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

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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 to be considered when designing and executing pivotal clinical
trials for 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.