What is fixed dose combination

The advantages of fixed-dose combinations are well recognized but their formulation and manufacture can be a challenge, Stefania Barzanti from IMA Active explains why.

Developing fixed-dose combinations (FDCs) is one of the many reformulation strategies used in product lifecycle management. It has the potential to offer quicker commercial returns compared to developing a new chemical entity. For pharmaceutical companies seeking to maximize the value of their drug products, FDCs can provide a means of obtaining supplementary patent protection and differentiating against cheaper generic-drug formulations. These formulations have shown success in the treatment of cardiovascular diseases, diabetes, HIV/AIDS, tuberculosis, and malaria.

Drivers for FDCs
“FDCs can be used either to combine different actives in one single dosage form or to achieve a precise release profile of a specific active-for example, by combining an immediate-release with an extended-release formulation,” explains Stefania Barzanti, marketing manager at IMA Active division. According to her, the success of FDCs is driven by two concurrent needs. “On one side, there is the need for welfare systems to contain healthcare costs; and on the other side, the need for pharmaceutical companies to optimize product lifecycle and exploit the potential of their existing product portfolio,” she says. FDCs are more cost-effective than individual drugs administered separately. They are known for their ability to reduce the pill burden. It is presumed that the simplification of therapy and its convenience lead to better overall patient compliance. The other main advantage of FDCs is the enhanced efficacy and lower incidence of side effects as a result of the synergistic combination of potentially lower doses of the different actives.

Developing an FDC, however, requires careful assessment of the potential advantages against the possible disadvantages, such as the difficulty or inflexibility of dose titration. “It is true that the flexibility in dosing options is reduced with FDCs, and it becomes more difficult to have fine tuning of the medication prescription to the needs of a specific patient,” Barzanti notes. “That’s why careful evaluation of the pros and cons of developing an FDC should drive the choice between the different solutions on the basis of a patient-centric approach that considers lifestyle needs and the medical condition.”

Drug developers are required to justify the pharmacological and medical rationale behind each FDC for the intended therapeutic indication. According to the European Medicines Agency, the rationale should consider the posology and dosing frequency of the different components included in the FDC (1).

Formulation and manufacturing challenges
“In terms of formulation, the first challenge is to bring together the different pharmacokinetic and target-release profiles,” says Barzanti. “This task, of course, becomes more complex with a higher number of active drugs.” The actives in the FDC must be assessed for physical and chemical compatibility, along with their excipients, to ensure that the different components do not generate new impurities or raise unfavorable drug–drug interactions.

“From the manufacturing point of view, however, one of the most common challenges is represented by the combination of two chemically incompatible actives that have to be kept separated but included into a single dosage form,” observes Barzanti. She explains that this issue is particularly crucial for layered tablets, where sometimes an intermediate placebo layer has to be created to avoid any interaction. “During tableting, constant checks and frequent replacement of the scraper blade are also important to avoid mixing of the different powders comprising the various layers.”

Another particularly relevant issue is represented by the control of the dosage of each drug, according to Barzanti. “In a layered tablet, the single layers can be sampled and checked individually on a statistic base, but it is not possible to check them separately in the final complete unit dose,” she says. “During the past four to five years, we have seen a growing interest for hard gelatin capsules, specifically for FDC products. On a capsule filler, different ingredients can be easily combined inside the same capsule shell by simply adding a dosing unit. Besides powder, different product forms can also be dosed, including pellets and minitablets, small tablets or capsules, softgels or liquids, and semi-solids. There are technologies available for in-line check of each single unit produced by the machine.”

In some cases, FDCs can result in higher manufacturing costs because a more complex dosage form is being produced. Barzanti points out that the total cost to develop an FDC should include the subsequent manufacturing phases up to the final packaging. “But in any case, the final cost reduction from the increased patient compliance and better use of medicines makes FDCs beneficial when considering the cost aspect from a global standpoint,” she says.

“I see FDCs as one of many opportunities present on the market to innovate oral solid-dosage forms together with the growing interest for multiparticulate formulations and new drug-delivery solutions,” Barzanti continues. “The overall aim is to make better use of existing product portfolios through optimization of pharmacokinetics, improved bioavailability, and enhanced therapeutic effect, as well as minimization of side effects. FDCs can be especially useful to support long-term concurrent therapies in patients affected by chronic diseases that are related to each other. I believe the current aging population is a driver for growth for this type of oral solid-dosage form.”

Reference
1. EMA/CHMP/281825/2015, Guideline on Clinical Development of Fixed Combination Medicinal Products (London, April 2015).

Article DetailsPharmaceutical Technology Vol. 39, No. 12

Pages: 30–31

Citation: When referring to this article, please cite it as A. Siew, “Fixed-Dose Combinations,” Pharmaceutical Technology, 39 (12) 30–31 (2015).

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.