Treatment for Heart 
Failure: Endpoints for 
Drug Development 
Guidance for Industry 
 
 
 
DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within ___ days 
of publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit electronic comments to https://www.regulations.gov.  Submit written 
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, Rm. 1061, Rockville, MD  20852.  All comments should be identified with the 
docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document, contact Norman Stockbridge at 301-796-2240 or 
(CBER) Office of Communication, Outreach, and Development at 240-402-8010. 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
June 2019 
Clinical 
29477250dft.docx 
06/18/19   
Treatment for Heart 
Failure: Endpoints for 
Drug Development 
Guidance for Industry 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor 
Silver Spring, MD  20993-0002 
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
 
and/or 
 
Office of Communication, Outreach, and Development 
Center for Biologics Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 71, Room 3128 
Silver Spring, MD  20993-0002 
Phone: 800-835-4709 or 240-402-8010; Email: ocod@fda.hhs.gov 
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-
guidances 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
June 2019 
Clinical 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION..................................................................................................1 
II.  BACKGROUND ....................................................................................................2 
III.  MORTALITY DATA:  PURPOSE AND REQUIREMENTS ..........................3 
IV.  EFFICACY ENDPOINTS RELATED TO HOW PATIENTS FEEL AND 
FUNCTION ............................................................................................................4 
V.  HOSPITALIZATION AND OUTPATIENT INTERVENTION ......................4 
VI.  BIOMARKERS AND SURROGATE ENDPOINTS .........................................5 
VII.  ACUTE HEART FAILURE .................................................................................6 
VIII.  HEART FAILURE WITH PRESERVED EJECTION FRACTION ...............6 
IX.  HEART FAILURE IN THE PEDIATRIC POPULATION ..............................6 
 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Treatment for Heart Failure: Endpoints for Drug Development 
2  Guidance for Industry1 
3   
4   
5   
6  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
7  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
8  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
9  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
10  for this guidance as listed on the title page. 
11   
12   
13   
14  I.  INTRODUCTION  
15   
16  This guidance has two purposes: 1) to make it clear that an effect on symptoms or physical 
17  function, without a favorable effect on survival or risk of hospitalization, can be a basis for 
18  approving drugs2 to treat heart failure; and 2) to provide recommendations to sponsors on the 
19  need to assess mortality effects of drugs under development to treat heart failure.3 
20   
21  This guidance reflects the Food and Drug Administrations (FDAs) current thinking about 
22  developing drugs to treat heart failure.  Areas of uncertainty (highlighted in boxes in this 
23  guidance) remain, and FDA welcomes discussion and alternative approaches. 
24   
25  This guidance pertains primarily to treating chronic heart failure.  Development of drugs to treat 
26  acute heart failure and pediatric considerations are discussed briefly.  This guidance applies to 
27  both heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved 
28  ejection fraction (HFpEF). 
29   
30  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
31  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
32  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
33  the word should in Agency guidances means that something is suggested or recommended, but 
34  not required. 
35   
                                                 
1 This guidance has been prepared by the Division of Cardiovascular and Renal Products in the Center for Drug 
Evaluation and Research (CDER) in cooperation with the Center for Biologics Evaluation and Research (CBER) at 
the Food and Drug Administration. 
 
2 For the purposes of this guidance, all references to drugs include both human drugs and biological products unless 
otherwise specified. 
 
3 For purposes of this guidance, unless otherwise specified, references to drugs and drug products include drugs 
submitted for approval or approved under section 505(b) or (j) of the FD&C Act and biological products licensed 
under section 351 of the PHS Act, other than biological products that also meet the definition of a device in section 
201(h) of the FD&C Act (21 U.S.C. 321(h)). 
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
36  II.  BACKGROUND 
37   
38  Heart failure afflicts approximately 6.5 million patients in the United States and 26 million 
39  patients worldwide.  As the U.S. population ages, the prevalence of heart failure is increasing, 
40  with approximately 550,000 new cases diagnosed annually. 
41   
42  Heart failure causes substantial mortality and morbidity and has major effects on physical 
43  function and quality of life.  The annual mortality rate of patients with heart failure is 
44  approximately 10%.  Hospitalization is common, with approximately 30% of heart failure 
45  patients hospitalized annually.  Despite optimal management, most patients with heart failure 
46  have troublesome symptoms, including dyspnea and fatigue. 
47   
48  Drugs of several pharmacologic classes (angiotensin-converting enzyme (ACE) inhibitors, 
49  angiotensin receptor blockers (ARBs), beta blockers, mineralocorticoid receptor antagonists 
50  (MRAs)) that have been approved in the past 2 decades significantly improve heart failure 
51  outcomes, including physical function, risk of hospitalization, and survival, in patients with 
52  reduced ejection fraction.  Despite these therapies, the disease continues to shorten lives and 
53  cause significant disability and symptoms.  Diuretics, both thiazides and loop diuretics, are also 
54  widely used to reduce signs and symptoms of heart failure, although their outcome effects (death 
55  and risk of hospitalization) have not been evaluated.  These facts point to a need for new drugs to 
56  treat heart failure.  In addition, there are no effective treatments for HFpEF, which represents 
57  approximately 50% of heart failure cases. 
58   
59  Unfortunately, some drugs (e.g., milrinone and flosequinan) intended to treat heart failure were 
60  found to have favorable effects on exercise capacity and symptoms but were subsequently found 
61  to increase mortality.  This experience led FDA to ask sponsors to assess the mortality effects of 
62  such drugs, usually prior to approval.  The intent was not to require demonstration of improved 
63  survivalalthough that would be an important outcomebut rather to provide reasonable 
64  assurance that the drug did not increase mortality. 
65   
66  Subsequently, some sponsors and other stakeholders reported a belief that favorable effects on 
67  mortality and morbidity (specifically, hospitalization for heart failure) were required to approve 
68  drugs to treat heart failure.  The approvals of ACE inhibitors, ARBs, beta blockers, and 
69  sacubitril-valsartan may have contributed to this impression, as their approvals were based on 
70  these endpoints.  In fact, although important, favorable effects on survival and hospitalization 
71  rates are not required for FDA approval. 
72   
73  A drug that improves symptoms or function when added to standard of care would be valuable 
74  even if it did not improve survival or hospitalization.  Moreover, it is possible that if a drug 
75  provided substantial and persistent improvement in symptoms or function, especially for patients 
76  with New York Heart Association Class III or IV heart failure, some decrease in survival would 
77  be acceptable. 
78   
79  The type of evidence of effectiveness needed to support the approval of drugs to treat heart 
80  failure does not differ from the evidence needed to support the approval of drugs intended to 
2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
81  treat other conditions: substantial evidence demonstrating that the drug improves how a patient 
82  feels, functions (i.e., symptomatic or functional improvement), or survives. 
83   
84   
85  III.  MORTALITY DATA:  PURPOSE AND REQUIREMENTS 
86   
87  Mortality data can serve two purposes in the context of developing drugs to treat heart failure: 
88   
89  1)  As a primary efficacy endpoint, a decrease in mortality provides evidence of 
90  effectiveness in heart failure trials. 
91   
92  2)  As a safety endpoint, mortality data provides an assessment of the possibility of an 
93  adverse effect on survival. 
94   
95  When approval is based on improvement of symptoms or function, FDA will consider the 
96  following factors in determining whether and when (i.e., pre- or postapproval) additional 
97  mortality data are needed: 
98   
99    The mortality and other safety findings of pharmacologically similar drugs.  For 
100  example, the safety profiles of ACE inhibitors, ARBs, beta blockers, MRAs, and digoxin are 
101  well-established.  The safety of a new drug in these classes could be supported by existing 
102  data, and additional information on mortality might not be needed.  In general, drugs with 
103  novel mechanisms of action are more likely to require mortality data. 
104   
105    Planned duration of exposure.  If the planned treatment is for short-term use (typically less 
106  than 10 days), for example, treatment of acute exacerbations, there is generally no 
107  requirement for long-term mortality data. 
108   
109    The mortality and other safety findings of the drug in a closely related population in 
110  which at least a subset of the patients had heart failure or were at risk of heart failure.  
111  For example, many patients with coronary artery disease or long-standing diabetes have or 
112  will develop heart failure.  Results of studies in such populations could therefore support the 
113  safety of the drug in a heart failure population. 
114   
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
115   
116   FDA believes there should be further discussion about whether the nature, magnitude, and clinical 
117  importance of a symptomatic benefit, considered with the demonstrated risks, could justify deferral or 
118  omission of outcome studies to assess mortality.  
119   
120   When mortality data are needed, FDA believes it would be useful to discuss the risk of mortality that 
121  should be ruled out in outcome studies and whether the acceptable upper bound should be influenced by 
122  the drugs demonstrated benefits and risks.  
123   
124   FDA believes there should be discussion about whether and when an increased risk in mortality could be 
125  acceptable for a drug with an important symptomatic benefit. 
126   
127   
128  When a mortality study is needed, sponsors should consider simple outcome studies (i.e., with 
129  selective data collection, which are highly feasible in patients with heart failure, particularly 
130  those with advanced disease, because the mortality rate is high in such patients). 
131   
132   
133  IV.  EFFICACY ENDPOINTS RELATED TO HOW PATIENTS FEEL AND 
134  FUNCTION 
135   
136  Evidence of effectiveness for a heart failure drug could be based on improvements in symptoms 
137  (e.g., dyspnea, fatigue, edema) and/or function (e.g., walking, exercising, performing other 
138  activities of daily living). 
139   
140  Endpoints acceptable to FDA include individual symptoms or a composite symptom score, 
141  exercise capacity, functional capacity, New York Heart Association functional class, and 
142  measures of activity/daily living.  FDA will consider trials that use novel endpoints, including 
143  other clinical outcome assessments, other measures of functional capacity, and measures of daily 
144  activity (e.g., accelerometry data).  For endpoints that can be influenced by expectation bias or 
145  motivation (e.g., 6-minute Walk Test), blinding of investigators and subjects is critically 
146  important. 
147   
148  Sponsors should consult with the Agency early in the drug-development process to obtain 
149  agreement on proposed endpoints. 
150   
151  For guidance on patient-reported outcome measures, see the guidance for industry Patient-
152  Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims 
153  (December 2009). 
154   
155   
156  V.  HOSPITALIZATION AND OUTPATIENT INTERVENTION 
157   
158  Hospitalization represents an important clinical outcome, reflecting worsening function and/or 
159  symptoms, interruption of daily activities, and superimposed risks and inconveniences. 
160   
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
161  Hospitalization has been widely used as a measure of morbidity in trials of drugs for heart 
162  failure, either as an independent endpoint or as a component of a composite endpoint that 
163  includes mortality.  Typically, these endpoints have been assessed as time-to-first events. 
164   
165  Acceptable approaches to quantifying hospitalization (and outpatient interventions) for use as an 
166  endpoint include binary endpoints (hospitalization (yes/no)), number of hospitalizations, time-to-
167  initial hospitalization, time alive (or at home) and out of the hospital, and time to recurrent 
168  hospitalizations. 
169   
170   
171  The Agency encourages discussion of the pros and cons of capturing all-cause hospitalization versus 
172  cause-specific hospitalization. 
173   
174   
175  As heart failure treatment moves away from the inpatient setting, FDA will consider alternative 
176  endpoints that reflect clinically important worsening symptoms leading to an intervention (e.g., 
177  treatment in an emergency department, a same-day access clinic, or an infusion center) or 
178  unscheduled visits to a healthcare provider for administration of an intravenous diuretic. 
179   
180   
181  VI.  BIOMARKERS AND SURROGATE ENDPOINTS 
182   
183  To date, no biomarkers have been validated as surrogate endpoints for clinical benefit in heart 
184  failure.  For patients with symptomatic heart failure, it is generally possible to assess directly 
185  how individuals feel, function, and survive; therefore, biomarkers have little utility for evaluating 
186  drug efficacy in this setting.  Biomarkers, however, can be used to characterize risk in patients 
187  with heart failure (e.g., NT pro-BNP, left ventricular ejection fraction), and such measures can be 
188  useful for prognostic enrichment.  Moreover, biomarkers have utility for early proof-of-concept 
189  studies and, in particular, studies that serve as the basis for dose selection. 
190   
191  Where heart failure is a consequence of long-term myocardial damage (e.g., infiltrative 
192  cardiomyopathies), disease advancement can be slow, and there is great interest in therapies that 
193  may slow or prevent disease progression.  For such diseases, manifestations of a clinical benefit 
194  can take years to observe, and intermediate clinical endpoints and surrogate endpoints4 could 
195  support accelerated approval.  For example, consider a therapy that leads to a reduction, reversal, 
196  or prevention of myocardial infiltration.  A biomarker that assesses myocardial damage or 
197  infiltration, which is not a direct measure of clinical benefit, could be considered a reasonably 
198  likely surrogate endpoint5 to serve as the basis for accelerated approval if certain conditions are 
                                                 
4 See FDA-NIH BEST (Biomarkers, EndpointS, and other Tools) Resource for the definition of intermediate clinical 
endpoint and surrogate endpoint: 
https://www.ncbi.nlm.nih.gov/books/NBK453485/. 
 
5 See FDA-NIH BEST (Biomarkers, EndpointS, and other Tools) Resource for the definition of reasonably likely 
surrogate endpoint: 
https://www.ncbi.nlm.nih.gov/books/NBK453485/. 
5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
199  met (see the guidance for industry Expedited Programs for Serious Conditions  Drugs and 
200  Biologics (September 2017)), with subsequent verification of clinical benefit. 
201   
202   
203  VII.  ACUTE HEART FAILURE 
204   
205  Drugs developed with the intended indication of acute heart failure are generally targeted at 
206  acute exacerbations of chronic heart failure.  The duration of treatment is generally expected to 
207  be less than 10 days. 
208   
209  Such drugs could be approved based on symptom relief (e.g., dyspnea, time to hospital 
210  discharge, or avoidance of invasive therapies (left ventricular assist devices, dialysis)). 
211   
212  Safety must be assessed following drug administration (i.e., ascertainment of death and 
213  rehospitalization, generally through 30 days) for drugs with a short duration of exposure. 
214   
215   
216  VIII.  HEART FAILURE WITH PRESERVED EJECTION FRACTION 
217   
218  Although HFpEF and HFrEF are pathophysiologically distinct, the same considerations apply for 
219  both. 
220   
221   
222  IX.  HEART FAILURE IN THE PEDIATRIC POPULATION 
223   
224  Although a detailed discussion of heart failure in the pediatric population is out of scope of this 
225  guidance, many of the principles enumerated above apply to pediatric populations.  
226  Demonstration of clinical benefit may not be needed in pediatric patients with heart failure when 
227  the disease in pediatric patients is similar to that in adults and the drug is expected to exert the 
228  same effect irrespective of the underlying pathophysiology of heart failure (e.g., diuretics).  
229  There may, however, be unique safety considerations when developing drugs to treat heart 
230  failure in a pediatric population (e.g., effects on growth and development and hormonal 
231  changes). 
232   
233  Guidance documents specific to pediatric drug development should be consulted for additional 
234  information.  They include the following guidances for industry:  
235   
236    Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study 
237  Plans and Amended Initial Pediatric Study Plans (March 2016) 
238   
239    E11 Clinical Investigation of Medicinal Products in the Pediatric Population (December 
240  2000) 
241   
242    E11(R1) Addendum Clinical Investigation of Medicinal Products in the Pediatric 
243  Population (April 2018) 
6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
244    General Clinical Pharmacology Considerations for Pediatric Studies for Drugs and 
245  Biological Products (December 2014) 
246   
247    Nonclinical Safety Evaluation of Pediatric Drug Products (February 2006) 
7