Hypertension: Developing Fixed-Dose Combination Drugs for Treatment

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

Hypertension: Developing
Fixed-Combination Drug
Products for Treatment
Guidance for Industry
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
November 2018
Clinical/Medical

Hypertension: Developing
Fixed-Combination Drug
Products for Treatment
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)
November 2018
Clinical/Medical

TABLE OF CONTENTS
I. 	BACKGROUND AND INTRODUCTION..................................................................... 1
II. 	COMBINATION RATIONALE AND DEMONSTRATING CONTRIBUTION OF
COMPONENTS ................................................................................................................ 2
III. 	PHASE 3 TRIAL DESIGN AND LABELING CONSIDERATIONS ......................... 3

Contains Nonbinding Recommendations
1
Hypertension: Developing Fixed-Combination
Drug Products for Treatment
Guidance for Industry1
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) 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 FDA office responsible for this guidance as listed on the
title page.
I. 	BACKGROUND AND INTRODUCTION
The purpose of this guidance is to assist sponsors in the clinical development of fixed-
combination drug products2 for the treatment of hypertension. This guidance focuses on
development of two-drug combinations of previously approved drugs, although the general
approach is readily applicable to three or more drugs in combination. This guidance does not
address combinations that include unapproved drug products.
Hypertension is the most common chronic cardiovascular condition dealt with by primary care
physicians and other health care practitioners. Hypertension increases the risk of stroke, coronary
artery disease, heart failure, atrial fibrillation, and peripheral vascular disease.3, 4 Effective
control of blood pressure has been shown to reduce the rate of these adverse outcomes.
In general, most patients will require more than one drug product to achieve adequate blood
pressure control. In the past, the usual approach was to give patients the drug products
sequentially, that is, titrate the first drug product to its full dose, then add a second drug product
and titrate to its full dose, etc. More recently, physicians commonly initiate treatments with less
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.
2 For purposes of this guidance, a fixed-combination drug product is one in which two or more active ingredients are
combined at a fixed dosage in a single dosage form.
3 Rapsomaniki E, Timmis A, George J, et al., 2014, Blood Pressure and Incidence of Twelve Cardiovascular
Diseases: Lifetime Risks, Healthy Life-Years Lost, and Age-Specific Associations in 1·25 Million People, Lancet,
383:1899–1911.
4 Angeli F, Reboldi G, and Verdecchia P, 2014, Hypertension, Inflammation and Atrial Fibrillation, J Hypertens,
32(3):480–483.

Contains Nonbinding Recommendations
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than full doses of two drug products, with the goal of avoiding side effects but gaining most of
the effect of each drug product and gaining an overall effect greater than the single drug products
would have at their maximum doses. The American Society of Hypertension and the
International Society of Hypertension have jointly recommended initiating treatment with two
drug products if a patient’s untreated blood pressure is at least 20/10 millimeters of mercury
(mmHg) above the target blood pressure.5
In considering fixed-combination drug products, FDA recognizes the interest both in (1)
developing combinations of less than full doses of drug products with distinct mechanisms of
action (e.g., a diuretic combined with an angiotensin-converting enzyme inhibitor, an
angiotensin-receptor blocker, or a beta blocker) that could be used as initial therapy; and (2)
providing a range of combinations that allow dose titration to attain adequate blood pressure
control.
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
as recommendations, unless specific regulatory or statutory requirements are cited. The use of
the word should in Agency guidances means that something is suggested or recommended, but
not required.
II. COMBINATION RATIONALE AND DEMONSTRATING CONTRIBUTION OF
COMPONENTS
• 	In selecting drug products for use in fixed-combination drug products, sponsors should
consider previously approved antihypertensive drug products with reasonably distinct
mechanisms of action. Because of the different mechanisms of action, the drug products’
individual components used together are likely to demonstrate additive blood pressure
effects. In addition, if combinations include doses of each drug product below the
maximum dose, dose-related adverse effects of the components can be expected to be
reduced compared to uses of single drug products at their highest approved doses.
• 	For sponsors to establish safety and effectiveness of combination drug products, 21 CFR
300.50 (the combination rule) states that (1) each component must make a contribution to
the claimed effects; and (2) the dosage of each component (amount, frequency, duration)
is such that the combination is safe and effective for the intended patient population. In
the past, sponsors satisfied the combination rule for combination antihypertensive drug
products by examining the overall contribution of each drug in a large factorial study
using multiple doses of each component (e.g., A and B) and showing that A plus B is
greater than A and that A plus B is greater than B in an overall analysis of doses.
Alternatively to conducting full factorial studies of multiple doses of each component of
the combination, we believe a sponsor can demonstrate the independent contribution of
the components in two additional ways:
5 Weber MA, Schiffrin EL, White WB, et al., 2014, Clinical Practice Guidelines for the Management of
Hypertension in the Community: A Statement by the American Society of Hypertension and the International
Society of Hypertension, J Hypertens, 32(1):3–15.

Contains Nonbinding Recommendations
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— 	In a factorial study comparing A plus B to A and to B at their highest approved doses,
showing that each component contributes to the blood pressure effect, which shows
that there is a difference between the mechanisms by which the drug products exert
their effects.
— 	Alternatively, in a factorial study comparing A plus B to A and to B, at the highest
doses planned for the fixed-combination drug product (i.e., not necessarily the
highest approved doses), showing that each component contributes to the blood
pressure effect, provided that other evidence supports dissimilar mechanisms of action
and the doses in the combination are reasonably high on their dose-response curves.
• 	Once a sponsor addresses the combination rule with a study at the highest approved doses
or at the highest doses proposed for use in combination, the sponsor does not need to
study combinations of lower approved doses to satisfy the combination rule because the
drug products’ independent effects at lower doses can be assumed.
• 	Sponsors should adequately characterize the pharmacokinetics of each of the components
when used in combination.
• 	Sponsors that intend to market multiple dose combinations should pay attention to avoid
marketing excessive numbers of combinations whose components exert similar blood
pressure effects (e.g., a 5 mg/10 mg combination and a 7.5 mg/12.5 mg combination that
both produce similar decreases in blood pressure).
III. 	PHASE 3 TRIAL DESIGN AND LABELING CONSIDERATIONS
• 	In general, the FDA considers a single phase 3, double-blind, randomized trial to be
sufficient for demonstrating effectiveness of combination drug products of previously
approved antihypertensive drug products.
• 	The study intended to show an effect of both components should be carried out in a
population where initiating therapy with two drugs is appropriate. Sponsors should
consult contemporary treatment guidelines. The higher the baseline blood pressure, the
easier it will be to demonstrate blood pressure effects of the components, and the less
likely it is that there will be intolerance to blood pressure reduction.
• 	It is expected that significant effects are observed on both systolic and diastolic blood
pressures. The effects should be assessed at the end of the dosing interval.
• 	Sponsors should consider guidance intended to assist applicants in developing labeling
for cardiovascular outcome claims for drugs that are indicated to treat hypertension.6
6 See the guidance for industry Hypertension Indication: Drug Labeling for Cardiovascular Outcome Claims. We
update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA
guidance web page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.

Contains Nonbinding Recommendations
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• 	Sponsors should consider that labeling for two-drug combinations intended for initial use
frequently includes model-based figures, as shown below in Figure 1, that describe the
likelihood of reaching blood pressure goals on individual drug products or the
combination, as a function of the baseline blood pressure.
Figure 1: Probability of Achieving Systolic Blood Pressure Less Than 140 mmHg