Qualification of Biomarker Plasma Fibrinogen in Studies Examining Exacerbations and/or All-Cause Mortality in Patients With Chronic Obstructive Pulmonary Disease Guidance for Industry

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

Contains Nonbinding Recommendations
Qualification of BiomarkerPlasma Fibrinogen in Studies
Examining Exacerbations and/or All-Cause Mortality in Patients
With Chronic Obstructive Pulmonary Disease
Guidance for Industry
This guidance represents the current thinking of the Food and Drug Administration (FDA) on
this topic. It does not establish any rights for any person and is not binding on FDA or the
public. You can use an alternative approach if it satisfies the requirements of the applicable
statutes and regulations. To discuss an alternative approach, contact the Center for Drug
Evaluation and Research (CDER) Biomarker Qualification Program (email: CDER-
BiomarkerQualificationProgram@fda.hhs.gov).
Drug Development Tool (DDT) Type: Biomarker
Referenced Biomarker(s): Plasma fibrinogen
Fibrinogen is an acute phase protein that is elevated in inflammation. It is a soluble plasma
glycoprotein that is converted by thrombin to fibrin during blood clot formation.
I. SUMMARY OF GUIDANCE
A. 	Purpose of Guidance
This guidance provides a qualified context of use (COU) for the biomarker plasma fibrinogen, in
interventional clinical trials of patients with chronic obstructive pulmonary disease (COPD) at
high risk for exacerbations and/or all-cause mortality. This guidance also describes the
experimental conditions and constraints for which this biomarker is qualified through the CDER
Biomarker Qualification Program. This biomarker can be used by drug developers for the
qualified COU in submissions of investigational new drug applications (INDs), new drug
applications (NDAs), and biologics license applications (BLAs) without the relevant CDER
review group reconsidering and reconfirming the suitability of the biomarker.

Contains Nonbinding Recommendations
DDT Tracking Number: [DDTBMQ-000021]
2
B. 	Application of Guidance
This guidance applies to the use of plasma fibrinogen in investigational studies for exacerbations
and/or all-cause mortality in COPD patients. It does not change any regulatory status, decisions,
or labeling of any in vitro diagnostic test used in the medical care of patients.
Fibrinogen use in drug development outside of the qualified COU will be considered by FDA on
a case-by-case basis in regulatory submissions. In such cases, additional information relevant to
the expanded use may be requested by the CDER product review team.
II. CONTEXT OF USE
A. 	Use Statement
This guidance provides qualification recommendations for the use of plasma fibrinogen,
measured at baseline, as a prognostic biomarker to select patients with COPD at high risk for
exacerbations and/or all-cause mortality for inclusion in interventional clinical trials. 	This
biomarker should be considered with other demographic and clinical characteristics, including a
prior history of COPD exacerbations, as an enrichment factor in these trials.
B. 	Conditions for Qualified Use
1. 	Assay
An analytically validated assay should be used for measurement of plasma
fibrinogen. (Please see supporting documentation for details at Biomarker
Qualification Program: Qualified Biomarkers and Supporting Information.)
2. 	Plasma Fibrinogen-Based Patient Selection in Clinical Trials
a. 	P LASMA F IBRINOGEN LEVEL
The plasma fibrinogen level of patients selected for clinical trials should
be determined at baseline.
b. 	P ATIENT P OPULATION
Patients should have a clinical history of COPD as defined by the
American Thoracic Society/European Respiratory Society (ATS/ERS)
standards1 prior to enrollment, which involves a history of cigarette
smoking 10 pack-years or greater and obstructive lung physiology
1 ATS/ERS, 2004, Standards for the Diagnosis and Management of Patients with COPD, available on the Internet at
https://www.thoracic.org/copd-guidelines/resources/copddoc.pdf.

Contains Nonbinding Recommendations
DDT Tracking Number: [DDTBMQ-000021]
3
consistent with an increased risk for exacerbations and/or all-cause
mortality (i.e., Global Initiative for Chronic Obstructive Lung Disease
(GOLD Stage II or higher). Patients enrolled in COPD exacerbation trials
should also have a prior history of COPD exacerbations in the year prior
to enrollment in the clinical trial.
c. 	P ATIENT S ELECTION
Plasma fibrinogen can be used as an enrichment factor, in addition to
standard inclusion/exclusion criteria, in COPD clinical trials with
endpoints of COPD exacerbation and/or all-cause mortality.
Because fibrinogen was qualified using multiple assays, an optimal
enrichment threshold has not been determined. Therefore, a drug sponsor
should propose an appropriate threshold for a baseline plasma fibrinogen
level and discuss it with FDA during the protocol development phase.
(Please see supporting information for details at Biomarker Qualification
Program: Qualified Biomarkers and Supporting Information.)
d. 	M EASUREMENT APPLICABILITY
Fibrinogen was qualified primarily based on the Evaluation of COPD
Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE)
study data that used an immunological assay that measured a range of
fibrinogen concentrations between 100-900 milligrams/deciliter. Any
analytically validated method can be used to measure fibrinogen. (Please
see supporting information for details at Biomarker Qualification
Program: Qualified Biomarkers and Supporting Information.)
e. 	S AMPLE ACQUISITION AND DOCUMENTATION
Please follow the Clinical and Laboratory Standards Institute (CLSI) H21-
A5 recommendations2 for specimen collection, transport, and processing.
2 CLSI, 2008, Collection, Transport, and Processing of Blood Specimens for Testing Plasma-Based Coagulation
Assays and Molecular Hemostasis Assays; Approved GuidelineFifth Edition, H21-A5, 28(5).