Hypertension:  Conducting 
Studies of Drugs to Treat 
Patients on a Background of 
Multiple Antihypertensive Drugs 
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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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 60 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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 Stephen Grant at 301-796-2240.  
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
July 2018 
Clinical/Medical
22266711dft.doc 
06/26/18   
Hypertension:  Conducting 
Studies of Drugs to Treat 
Patients on a Background of 
Multiple Antihypertensive Drugs 
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/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
July 2018 
Clinical/Medical 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 1 
III.  PATHS TO APPROVAL OF ANTIHYPERTENSIVE DRUGS IN 
PATIENTS ON A BACKGROUND OF MULTIPLE 
ANTIHYPERTENSIVE DRUGS .................................................................................... 2 
 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Hypertension:  Conducting Studies of Drugs  
2  to Treat Patients on a Background  
3  of Multiple Antihypertensive Drugs 
4  Guidance for Industry1 
5   
6   
7   
8  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
9  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
10  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
11  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
12  for this guidance as listed on the title page. 
13   
14   
15   
16  I.  INTRODUCTION 
17   
18  This guidance is intended to clarify the recommended approach for sponsors developing drugs to 
19  treat hypertension for patients who are on a background of multiple antihypertensive drugs.   
20   
21  Sponsors have approached FDA to discuss development programs for drugs intended to treat 
22  resistant hypertension, which sponsors have defined as hypertension not adequately controlled 
23  by maximally tolerated doses of three or more antihypertensive drugs with different mechanisms 
24  of action.  FDA encourages development of additional classes of drugs for hypertension, 
25  particularly classes of drugs that demonstrate effects when added to currently available therapies. 
26   
27  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
28  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
29  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
30  the word should in Agency guidances means that something is suggested or recommended, but 
31  not required. 
32   
33   
34  II.  BACKGROUND 
35   
36  Elevated blood pressure increases the risk of stroke, cardiovascular death, heart failure, and 
37  myocardial infarction.  Drugs that lower blood pressure have been shown to reduce these risks 
38  significantly.  
39   
40  FDA has approved many drugs to lower blood pressure (antihypertensive drugs).  These drugs 
41  have a variety of mechanisms of action.  Antihypertensive drugs are uniformly labeled for use 
42  alone or in combination with other antihypertensive agents, reflecting the fact that adding an 
                                                 
1 This guidance has been prepared by the Division of Cardiovascular and Renal Products in the Center for Drug 
Evaluation and Research at the Food and Drug Administration.  
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
43  antihypertensive drug to another antihypertensive drug with a different mechanism of action is 
44  expected to result in further reduction of blood pressure. 
45   
46  The labeling for antihypertensive drugs does not identify a target blood pressure goal but rather 
47  refers prescribers to published guidelines.  The target blood pressure goals and the sequence of 
48  drugs recommended to get patients to those goals vary among guidelines and have evolved over 
49  time as new antihypertensive drugs of various pharmacologic classes have become available 
50  since the term antihypertensive was first used in the 1970s and as new outcome data have 
51  become available. 
52   
53  At present, the most commonly recommended drug classes for initial therapy of hypertension are 
54  diuretics, renin-angiotensin system inhibitors, beta blockers, and calcium channel blockers, or a 
55  combination of these.  Other possible treatments include aldosterone antagonists, alpha blockers, 
56  central alpha agonists, and direct vasodilators.  Nevertheless, availability of additional 
57  antihypertensive drugs with novel mechanisms of action would be valuable.  
58   
59  The term resistant hypertension occasionally has been used to describe a patient whose blood 
60  pressure is inadequately controlled despite being on three or more antihypertensive drugs.  
61  However, the specific term has no clear meaning and does not describe a clear patient subset. As 
62  noted, many patients will need two, three, or four antihypertensive drugs to achieve adequate 
63  control of blood pressure.  Although FDA will not label a drug with a specific claim for resistant 
64  hypertension, FDA does believe that drugs could be shown to be effective in treating 
65  hypertension in patients already on a background of multiple antihypertensive drugs.  
66   
67   
68  III.  PATHS TO APPROVAL OF ANTIHYPERTENSIVE DRUGS IN PATIENTS ON 
69  A BACKGROUND OF MULTIPLE ANTIHYPERTENSIVE DRUGS 
70   
71  Development in this area is not fundamentally different from standard development of 
72  antihypertensive drugs.  Sponsors have at least two paths to obtain approval of drugs intended to 
73  treat hypertension in patients on a background of multiple antihypertensive drugs:   
74   
75    Demonstrate superiority to placebo in reducing blood pressure in hypertensive patients on 
76  appropriate doses of three or more antihypertensive drugs with different mechanisms of 
77  action.  This would result in a claim that the new drug is indicated for the treatment of 
78  hypertension, to lower blood pressure.  The background medications and the range of 
79  doses taken during the study, as well as the added effect of the new drug, would be 
80  described in the CLINICAL STUDIES section of the resulting labeling. 
81   
82    Demonstrate superiority to another (or more than one) antihypertensive drug (active 
83  comparator) in reducing blood pressure in hypertensive patients already receiving 
84  maximum doses of three or more antihypertensive drugs with different mechanisms of 
85  action.  This would result in a claim that the new drug is superior to the specific active 
86  comparator drug for the treatment of hypertension, to lower blood pressure.  The active 
87  comparator should differ in mechanism of action from the mechanisms of the background 
88  medications, and the dose(s) of the active comparator would have to be the maximum 
2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
89  dose.  The background medications and the range of doses taken during the study would 
90  be described in the CLINICAL STUDIES section of the resulting labeling. 
91   
92   
3