- 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a draft guidance for industry entitled "Efficacy Studies to Support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the draft guidance document was too restrictive with regard to the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.
Table of Contents
- 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 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.
Table of Contents
- 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 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:
- Fibrin sealant products should be tested in settings and under
conditions where they would normally be expected to be used in
clinical practice.
- Fibrin sealant products may be tested against a placebo, a
cleared hemostatic device, or other control, as appropriate.
- Efficacy of fibrin sealant products may be tested by using
either hemostasis endpoints or other measures of clinical
benefit, depending on the indications sought.
