Fixed-dose combination products (FDCs), or drugs containing multiple active ingredients, offer benefits to pharmaceutical companies and patients. For Pharma, creative matching of multiple APIs can open new markets, while for patients, FDCs can offer convenience and therapeutic benefits. Often, FDCs are composed of previously approved agents, and the 505(b)(2) pathway is commonly used for these approvals. While utilizing the 505(b)(2) pathway often leads to smaller development programs, Sponsors should be aware of requirements for combination products to show that each active component of the combination contributes to the overall efficacy of the product.

Last year, Kwon and Lee published an analysis of recent trends in fixed-dose combination product NDA approvals between 2010-2015 (Kwon and Lee, 2016) In total, during this time, 63 FDCs were approved, making up 9.6% of the total drug products approved by the FDA. Even though the majority of approvals used the 505(b)(2) pathway (52%), when all FDC approvals were considered, the majority (51%) were still required to perform Phase 2 and 3 studies. We have observed similar trends for 505(b)(2) combination products.

The Combination Rule

Using Premier Consulting’s proprietary database, we have determined that two-thirds of all FDCs approved by the 505(b)(2) route to date required at least one Phase 2 or Phase 3 study, and approximately one-third required more than 4 Phase 2/3 studies.

On the surface, these results are somewhat surprising, since most combination products are composed of previously approved drugs. However, combination products are subject to the “Combination Rule,” which requires that combination products demonstrate the contribution of each active component to the drug’s claimed effects. For Sponsors, this typically means conducting a Phase 3 efficacy study to compare the effects of monotherapy to combined therapy.

A recent 505(b)(2) NDA approval provides an example of the Combination Rule in action.

Case study – Byvalson (Contribution of Active Components)

Hypertension continues to be a significant public health concern in the US and worldwide. To treat hypertension and prevent subsequent cardiovascular morbidity and mortality, a number of therapeutic classes of drugs are used, including diuretics, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), calcium channel blockers, and aldosterone antagonists. These pharmacological agents are typically indicated when hypertension is not controlled by lifestyle modifications. While patients are typically started with monotherapy treatment, if target blood pressure is not achieved, doctors will either increase the dose of the monotherapy or add an additional pharmacological treatment to the regimen, typically an agent with a different mechanism of action.

Byvalson was designed with this strategy in mind. Byvalson consists of nebivolol (a beta blocker) and valsartan (an ARB). Valsartan and nebivolol were both previously approved (as Bystolic in 2007 and Diovan in 1996, respectively), for use in hypertension. Nebivolol and valsartan have a range of doses for monotherapy use; 2.5, 5, 10, and 20 mg tablets for nebivolol, and 80 and 160 mg capsules for valsartan.

The initial Byvalson NDA submission included FDCs of nebivolol/valsartan of 5/80 mg, 5/160, 10/160 mg, 10/320 mg and 20/320 mg tablets. In support of safety and efficacy, the Sponsor had performed a multicenter, double-blind, randomized, placebo-controlled, parallel group fixed-dose combination pivotal Phase 3 study to assess the combination treatments in comparison to nebivolol or valsartan monotherapy. Eight treatment arms were used, with low dose treatment that was doubled after 4 weeks (nebivolol monotherapy 5 [10] mg, 20 [40] mg, valsartan monotherapy 80 [160] mg, 160 [320] mg, FDC 5/80 [10/160] mg, 5/160 [10/320] mg, 10/160 [20/320] mg, and placebo). While all treatment arms demonstrated effectiveness at reducing blood pressure, the improvement in efficacy of the FDCs over the maximum dose of nebivolol monotherapy was minimal, calling into question the clinical relevance of Byvalson. The Sponsor argued that there was an improvement when Byvalson was compared to valsartan monotherapy, but the reviewing FDA Division (the Division of Cardiovascular and Renal Products) stated there was no regulatory precedent to approve an FDC based on improved efficacy relative to only one of the 2 FDC components. This issue ultimately led to a Complete Response letter to Forrest Laboratories in December 2014, based on the conclusion that Byvalson’s effect was too small, without an improved safety advantage.

During the time that Byvalson was under review, the paradigm of approving FDCs for treatment of hypertension was discussed at a Cardiovascular and Renal Drugs Advisory Committee meeting. In this meeting, data was presented from a meta-analysis of 354 randomized trials to assess the effectiveness of anti-hypertensive medications used as monotherapy or in combination. Across pharmacologic classes, at half of the standard dose, only a 20% lower effect than the standard dose was observed, suggesting that increased doses of anti-hypertensives used in monotherapy may not lead to proportional effects in efficacy. However, if half-doses of multiple anti-hypertensive agents (of unique MOAs) were used in combination, near additive therapeutic effects occurred. These results suggested that there was little to be gained in blood pressure reduction with increased dose of monotherapy compared with a low-dose combination. However, a FDC using lower doses of individual agents in combination may provide an efficacy and safety advantage.

Based on the conclusions of this advisory committee, the Agency provided guidance to the Sponsor for how to move the Byvalson program forward. Based on the data that a low-dose combination of anti-hypertensive treatments with sufficiently distinct mechanisms of action have additive effects on efficacy, low-dose treatment in combination would be expected to mitigate dose-related adverse effects, and thereby result in better tolerability along with equal or enhanced efficacy. This was an unprecedented suggestion by the Division, but they said that they were willing to consider this option, even in the absence of improved tolerability data.

Additive Effects Contribution

With this in mind, the Sponsor resubmitted the Byvalson NDA with a re-analysis of the Phase 3 trial data. From a safety and tolerability perspective, the 5/80 mg FDC was well tolerated, with no greater risk of adverse events in FDC groups compared with the respective monotherapy groups. In regards to efficacy, the 5/80 mg combination had statistically and clinically significantly greater reduction in blood pressure compared to respective nebivolol or valsartan monotherapy, showing that each of the components make a contribution to the claimed effect at that dose. Additionally, near additive effects were observed with the 5/80 mg FDC. To further support the additivity effect, the Sponsor evaluated the Division’s prior assessments of antihypertensive combinations. The Sponsor compared the additivity ratio and additivity difference of the 5/80 mg product to previously approved hypertensive combination products, and showed that the additivity measures of Byvalstan 5/80 mg were within the range of previously approved FDCs. Based on these conclusions, Byvalson 5/80 mg was approved in 2016, becoming the first beta blocker/ARB combination for the treatment of hypertension.

Our experts at Premier Consulting have extensive experience with FDC products and the regulatory standards that these products must meet. Let us help you find the best regulatory strategy for the most efficient route to market. Contact us to find out more.