Fixed-dose combination (FDC) drugs, a growing market that combines multiple active pharmaceutical ingredients (APIs) into a single-dose product, aim to improve patient convenience, compliance, and appropriate dosing. Pharma companies can realize substantial savings when developing an FDC comprised of previously approved new chemical entities or their generic counterparts. FDC products have proven to be an attractive strategy for extending the market potential of proprietary drugs.
 
Halo Pharma has provided technical expertise and formulation technology to support the development and manufacture of FDC drugs that are currently approved, as well as in development, as part of an effort to reduce costs, time to market, and extend market dominance. Dr. Anthony Qu, vice president of scientific affairs at Halo Pharmaceuticals provides insight into the advantages and opportunities of FDC drug products.

Contract Pharma: What makes FDC so attractive for Pharmaceutical companies?
 
Anthony Qu: FDCs are a potentially attractive way to repurpose APIs in combinations that solve unmet clinical needs. FDC’s could enable additional protection of intellectual property and extended market exclusivity in some cases. This is because FDCs are composed of previously approved agents. 
 
Some companies choose the 505(b)(2) pathway for shorter development programs for approval of FDCs. Using this pathway may lead to value creation for the pharma company through marketing of a new product under an NDA instead of an ANDA but without the long lead-time and expense of a full clinical program.
 
From a patient perspective, FDCs are attractive because the pharma company may be able to offer a lower therapeutic dose of two drugs in one product that may be more effective than a higher dose of a single drug. FDCs may also minimize adverse effects when given in combination and at lower doses that contain two or more APIs. In addition, the simplification of the treatment regimen is a patient benefit where fewer pills taken means better patient adherence to dosing instructions and compliance.
 
CP: What are some examples of formulation options for FDC?
 
AQ: Because Halo possesses a wide range of formulation capabilities, our clients can choose from multilayer tablets, or even mini-tablets that can be compressed together or combined into capsules, sachets, or stick-packs. Halo offers a variety of polymer-coating options to enable controlled release of differing drug substances in one tablet, as well as taste-masking methods that rely on ion exchange technology. This range of options is enabled by the flexibility and variety of manufacturing platforms at Halo. Customers can choose the FDC solid dose form that is most suitable for their clinical needs. Our process capabilities include not only hot melt extrusion, wet or dry granulation, roller compaction, extrusion-spheronization in addition to multiparticulate capsule filling and bilayer press capabilities suitable for FDCs.
 
We have seen a marked interest in FDC products from current and new customers. The capabilities Halo offers, all under one roof, provide many options for customers in the development of their products. Halo is one of only a select group of CDMOs that have both development and commercial manufacturing experience in FDCs. We have made, and will continue to make, significant investments in equipment and technical expertise to support this capability.
 
CP: Please provide an example of using the 505(b)(2) pathway
 
AQ: Based on published data from the U.S. FDA, there were 63 FDCs among 655 NDA approvals[i] (2010-2015), and the majority of those FDC approvals followed the 505(b)(2) pathway, rather than completion of all phases of clinical trials required under NCE programs.
 
The following are two examples of approved FDCs that benefitted from 505(b)(2). For the treatment of diabetes, Actoplus MET XR is a combination of pioglitazone and metformin.
For the treatment of hypertension, Azor is a combination of amlodipine and olmesartan.
 
Drugs are often combined due to their respective pharmacokinetics (PK) and metabolic profiles. A pharma company might be able to pursue the 505(b)(2) pathway for single combination product approval of two statins that lower LDL and HDL cholesterol if both statins are individually approved at the same dose.

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[i] Kwon KC Lee C. Analysis of Fixed-Dose Combination Products Approved by the US Food and Drug Administration, 2010-2015. Implications for Designing a Regulatory Shortcut to New Drug Application. Ther Innov & Reg Sci 2017;51:111-117
 

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 Dr. Anthony Qu

Dr. Anthony Qu is vice president of scientific affairs at Halo Pharmaceuticals. In this role, Anthony leverages more than two decades of research and development experience in brand, generic and contract pharma companies to help clients develop and transfer their molecules from earlier phase to commercialize drug products. He works with his product development team and has successfully developed and transferred multiple fixed dose combination products.