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The Hypertension Fixed-dose Combination Product Guidance: Straight from the 505(b)(2) Playbook

The FDA just released a new draft guidance on developing fixed-dose combination antihypertensive products. While the clarification for industry is good, the strategy is not new to Premier Consulting.

Gaining approval of a combination product that is made up of approved, single-entity drugs is achieved via the 505(b)(2) pathway. So it is not surprising that the studies and strategies outlined by the FDA in the draft Hypertension: Developing Fixed-Dose Combination Drugs for Treatment Guidance are familiar to the 505(b)(2) experts.

Actually, the new draft guidance validates the antihypertensive drug development programs that Premier Consulting has been presenting to our Sponsors and to the FDA for the last 14 years. The guidance outlines a general requirement for only one Phase 3 study if each of the actives are already approved. We have already done better than that by gaining the FDAs concurrence on a BE-only program for an antihypertensive fixed-dose combination containing a new chemical entity!

Why the Guidance?

Although most of the current antihypertensive drugs were developed as single-entity products, the current standard of care (as published jointly by the American Society of Hypertension and the International Society of Hypertension) for patients with untreated blood pressure of greater than or equal to 160/100 mmHg is initiation of treatment with 2 drugs.

The rationale is that greater treatment effect with less side effects occur with combinations of drugs that have distinct mechanisms of action than either drug at higher doses. The FDA recognizes Sponsor interest in developing these combination antihypertensive products.

The issue is that to gain approval for a product with more than one active ingredient, a Sponsor must satisfy the “Combination Rule” (21 CFR Section 300.50: Fixed-combination Prescription Drugs for Humans), as we have described in previous blogs (here and here).

Essentially, this means that each drug must be demonstrated to contribute to the effect of the combined product. This is often achieved through clinical factorial studies comparing each drug alone and in combination. These are often very large studies with many treatment arms.

In the case of well-studied antihypertensives that are already used in combination as part of the standard of care, the new draft Guidance clarifies a more streamlined pathway to approval.

505(b)(2) Combination Hypertensives Approved To-Date

Eleven fixed-dose combination products have been approved since 2006 via the 505(b)(2) pathway, including 3 triple combinations. Nonclinical studies were conducted for 6 of these products, although often the FDA did not require nonclinical studies due to the extensive clinical experience with these products alone and in combination.

An average of 4 efficacy and/or safety studies were conducted for the 11 fixed-dose combination products, in one case as many as 9 studies were conducted. In fact, in this approval for a 3-drug combination product, 6 of the studies were designed to address the combination rule by comparing double and triple combinations.

Hypertension studies typically enroll over a thousand patients. That’s a lot of patients and a lot of studies for well-known combinations of antihypertensive drugs, hence the FDA’s issuance of Guidance.

New Recommendations in the Fixed-Dose Combination Antihypertensive Guidance

To address the combination rule, the FDA has clarified that as an alternative to full factorial studies, sponsors of multi-drug antihypertensive products may conduct either of the following partial factorial studies:

  1. Compare Drug A + B to Drug A and to Drug B at their highest approved doses, or,
  2. Compare Drug A + B to Drug A and to Drug B at the highest doses planned for the fixed combination.

If the Sponsor chooses the first option, compliance with the combination rule at lower doses will be assumed, as long as there is evidence for different mechanisms of action, and the doses in the combination are reasonably high on their dose-response curves.

Additionally, the draft Guidance states that a single Phase 3 double-blind, randomized trial will generally be sufficient for demonstrating effectiveness of combination drugs of previously approved antihypertensive drugs. Of course, the study population should be appropriate, and the endpoints prespecified.

Premier Consulting’s Antihypertensive Experience

Premier Consulting has worked on more than 111 fixed-dose combination products over the years, including 25 three-drug and four-drug combinations for a total of 51 FDA meetings.

We have used the alternative approaches mentioned in the draft guidance for many years prior to its release. Specifically, we have successfully made the case for comparing Drug A + B to Drug A and to Drug B at their highest approved doses.

In fact, we like to think that the groundwork that we have put in for our clients in proposing and justifying alternatives to full factorial studies has contributed to creating the shift in the FDAs thinking on the topic.

After all, we work closely with the FDA to explore novel approaches to reduce the size and scope of the clinical (and nonclinical) development programs for Sponsors. Premier Consulting meets with the FDA several times per month, placing us at the cutting edge of drug development.

In a recent meeting with the FDA to discuss a fixed-dose combination antihypertensive product, Premier Consulting gained concurrence from the FDA on a bioequivalence (BE)-only program without the need for conducting a Phase 3 trial. In this case, one of the active ingredients is a new molecular entity and a metabolite of an approved antihypertensive prodrug.

This highlights that there are exceptions to the Phase 3 requirement, but that extensive experience with 505(b)(2) programs, and in this case familiarity with prodrug/metabolite regulatory requirements, is needed to use this to advantage. Our proposed BE-only program was based on in-depth research and strong rationale. This was a huge win in time to market and cost for the Sponsor who was expecting to conduct a full factorial Phase 3 program.

So don’t assume a full factorial study/ies are required for approval of your fixed-dose combination product. Premier Consulting welcomes the opportunity to evaluate your drug development program, especially for fixed-dose combinations containing 2, 3, or more drugs. Our in-house pharmacokinetic, clinical, nonclinical, CMC, and regulatory experts work together to come up with flexible and novel solutions for each product.

With Premier Consulting’s 505(b)(2) experience, we make fundamental value changes to a Sponsor’s original planned budget and timeline.

Contact us to discuss your needs.


Angela Drew, PhD
Product Ideation Consultant

Ruth E. Stevens, PhD, MBA
Strategic Advisor