Hypertension: FDA Drafts Guidance on Two-Drug Combinations of Previously Approved Drugs
The US Food and Drug Administration (FDA) on Thursday released draft guidance to help sponsors develop fixed-dose combination drugs to treat hypertension, and more specifically, two-drug combinations of previously approved drugs.Hypertension, according to FDA, is the most common chronic cardiovascular condition dealt with by primary care physicians and other health care practitioners.
The 7-page draft, which features sections on combination rationale and Phase 3 trial design, does not address combinations of unapproved drugs.
FDA said it “recognizes the interest both in: (1) developing combinations of less than full doses of drugs 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 selecting drugs for the fixed combinations, FDA says sponsors should consider previously approved antihypertensive drugs with reasonably distinct mechanisms of action.
“For sponsors to establish safety and effectiveness of combination drugs, 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 drugs 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 A plus B is greater than B in an overall analysis of doses,” the draft says.
FDA also offers two alternatives to conducting full factorial studies of multiple doses of each component:
- “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, which shows that there is not complete overlap of the mechanisms by which the drugs exert their effects.
- Alternatively, 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.”