Contains Nonbinding Recommendations 
 
 
Qualification of BiomarkerPlasma 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]     
 
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.  PLASMA FIBRINOGEN LEVEL 
 
The plasma fibrinogen level of patients selected for clinical trials should 
be determined at baseline. 
 
b.  PATIENT POPULATION  
 
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. 
2 
  Contains Nonbinding Recommendations 
 
DDT Tracking Number:  [DDTBMQ-000021]     
 
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.  PATIENT SELECTION 
 
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.  MEASUREMENT 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.  SAMPLE 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 GuidelineFifth Edition, H21-A5, 28(5).  
3