On January 25, 2018, FDA issued draft guidance on developing fixed-dose combination drugs for treating hypertension. The guidance concerns development of combinations of two or more previously approved drugs, but does not address combinations that include unapproved drugs.
Hypertension, the most common chronic cardiovascular condition, increases the risk of other cardiovascular conditions such as stroke, coronary artery disease, heart failure, atrial fibrillation, and peripheral vascular disease. These cardiovascular risks can be reduced by effectively controlling blood pressure. The American Society of Hypertension (ASH) and the International Society of Hypertension (ISH) have jointly recommended initiating treatment with two antihypertensive drugs if a patient’s untreated blood pressure is at least 20/10 mmHg above the target blood pressure.
For combination antihypertensive drugs, the guidance recommends selecting previously approved antihypertensive drugs with reasonably distinct mechanisms of action to increase additive blood pressure effects while reducing dose-related adverse effects. The rule governing fixed-combination prescription drugs, 21 CFR § 300.50, provides that each component must make a contribution to the claimed effects, and that the dosage of each component be such that the combination is safe and effective for the intended patient population. While sponsors have previously satisfied the combination rule’s requirements by conducting full factorial studies of multiple doses of each component of the combination, the guidance provides two additional ways to satisfy the rule:
(1) In a factorial study comparing A+B to A and to B at their highest-approved doses, showing that each component contributes to the blood pressure effect; or
(2) In a factorial study comparing A+B to A and to B, at the highest doses planned for the fixed combination, 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.
Upon completing either of the above factorial studies, a sponsor would not need to study combinations of lower approved doses to satisfy the combination rule, because the drugs’ independent effects at lower doses can be assumed.
For clinical trial design, the guidance provides that a single phase 3, double-blind, randomized trial would generally be sufficient to demonstrate effectiveness of a combination of previously approved antihypertensive drugs. The guidance recommends that sponsors carry out the study in an appropriate population based on contemporary treatment guidelines, and specify in advance the primary endpoint (i.e., systolic, diastolic, or mean blood pressure).
The guidance also recommends that sponsors review the related FDA guidance on labeling for hypertension indications. In particular, the guidance suggests sponsors consider that labeling for two-drug combinations frequently includes model-based figures, such as the following Figure 1, reproduced from the guidance.