The US Food and Drug Administration (FDA) on Tuesday finalized guidance on developing fixed-combination drugs to treat hypertension.
The guidance, which finalizes a draft version
released in January, focuses on the clinical development of two-drug combinations of previously approved products and has been updated primarily for editorial changes.
According to FDA, most hypertension patients will require more than one drug to adequately control their blood pressure. While in the past physicians typically started a patient on a single drug and titrated up to a maximum dose before adding additional drugs to their regimen, current guidelines recommend starting patients on two drugs at less than their full doses.
“FDA recognizes the interest both in developing combinations of less than full doses of drug products with distinct mechanisms of action … that could be used as initial therapy; and providing a range of combinations that allow dose titration to attain adequate blood pressure control,” FDA writes.
While the guidance focuses on two-drug combinations, FDA says that the approach described in the guidance “is readily applicable to three or more drugs in combination,” but does not cover combinations that include investigational drugs.
When considering which drug products to include in a fixed combination, FDA says that sponsors should select products “with reasonably distinct mechanisms of action” as they are likely to have additive effects compared to two drugs with similar mechanisms of action.
FDA also says it would expect to see reduced adverse effects for combinations that include doses below each drugs’ maximum dose compared to single drug regimens at their maximum dose.
Under 21 CFR 300.50, also known as the “combination rule”, sponsors must show that each component of a combination makes a “contribution to the claimed effects” and that 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, FDA says that sponsors have typically done so for antihypertensive drugs by studying the contribution of each drug at multiple doses in a large factorial study “showing that A plus B is greater than A and that A plus B is greater than B in an overall analysis of doses.”
FDA also offers two alternatives to this method, one being to conduct a factorial study comparing the two drugs in combination to the highest approved dose of each drug independently and the other being to compare the two drugs in combination to the “highest doses planned for the fixed-combination drug product.”
Regardless of the approach taken, FDA says that a single Phase III, double-blind, randomized trial is sufficient to demonstrate effectiveness and that the study should be conducted in a population where initiating therapy with a two-drug regimen would be appropriate.
, Federal Register Notice