Hypertension: US FDA Issues Guidance on Developing FDC Drugs

The US FDA has now issued guidance on developing fixed-dose combination (FDC) drugs for the treatment of hypertension. This follows the increase in hypertension among the worldwide population and requirement for more FDCs.

The purpose behind this guidance is to support in the clinical development of FDCs for the treatment of hypertension. The guidance focuses on the development of two-drug combinations of previously approved drugs, although the general approach is readily relevant to three or more drugs in combination. This guideline does not address combinations that include unapproved drugs.

Hypertension is the most common chronic cardiovascular condition dealt with by primary care doctors and other healthcare practitioners. It increases the risk of stroke, coronary artery disease, heart failure, atrial fibrillation, and peripheral vascular disease. Effective control of blood pressure has been demonstrated to reduce the rate of these adverse results.

Generally, most patients will require more than one drug to achieve adequate blood pressure control. In considering fixed combinations, FDA perceives the interest both in developing combinations of not as much as full doses of drugs with distinct mechanisms like a diuretic combined with an angiotensin-converting enzyme inhibitor, or a beta blocker that could be used as initial therapy.

The second is to provide a range of combinations that allow dose titration to adequate blood pressure control. In choosing drugs for use in fixed combinations, sponsors should consider previously approved antihypertensive drugs with reasonably distinct mechanisms of action.

As a result of the different mechanisms of action, the drug components used together are probably going to show additive blood pressure effects. Additionally, if combinations include doses of each drug below the maximum dose, dose-related adverse effects of the components can be expected to be reduced compared with uses of single drugs at their highest approved doses.

Once a support addresses to the combination rule with a research at the highest approved doses or at the highest doses proposed for use in combination, the sponsor does not have to study combinations of lower approved doses to fulfill the combination rule because the drugs independent effects at lower doses can be assumed, said the regulator.

Sponsors should adequately characterize the pharmacokinetics of each of the components when used in combination. The FDA encourages sponsors to market dose combinations that represent clinically significant titration steps.

Generally, the global regulatory authority considers a single phase 3, double-blind, randomized trial to be 100 sufficient for demonstrating the effectiveness of combination drugs of previously approved antihypertensive medications.

 

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