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    Features

    FDCs on the Rise

    Fixed-dose combination drugs continue to gain traction due to a multitude of benefits they offer, including speed to market a

    FDCs on the Rise
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    Betsy Louda, Associate Editor, Contract Pharma03.09.18
    Fixed-dose combination (FDC) drug products have made a splash in the pharmaceutical industry within the last decade. They serve as an increasingly attractive option for both patients and pharmaceutical companies alike, along with physicians, and even regulatory agencies. The reasons for that are certainly not lacking.

    The practice of combining two to three active pharmaceutical ingredients (APIs) to form one product brings the costs of developing and manufacturing multiple different drugs down to doing the same for just one. Additionally, FDC drug products are able to take advantage of the FDA’s 505(b)(2) approval pathway, which is a shortened clinical development program that can greatly cut down the length of time of approval. FDC drugs also cut costs for the consumer, combining what was once two or three copays into one.

    Improved patient compliance, more convenient dosing associated with improved clinical performance, and extended patent protection also make FDC drugs more attractive, however, these benefits should not be taken for granted. Producing safe, efficient, and effecting FDC drug products is no easy task. It requires experienced contract development and manufacturing organization (CDMO) partners combined with the latest industry technology.

    Halo Pharmaceutical is one such CDMO that includes FDC drug production within their manufacturing and scientific services. Contract Pharma spoke with the company’s chief executive officer, Lee Karras, along with their vice president of scientific affairs, Dr. Anthony Qu, about the benefits, challenges, and future of FDC drug products. 

    Contract Pharma: What major benefits do FDCs offer over other types of drug products?
    Anthony Qu: There are several benefits. First, let’s talk about it from a pharmaceutical company’s point of view. One of the benefits of fixed dose combination drugs is that as a company, you won’t have to spend billions and billions of dollars for development and lot of times to search new molecules. Instead, you can simply take existing molecules already approved on the market, and combine the two or three active ingredients together to make new products. In other words, it can dramatically shorten both timelines and dollars for a company to develop new products.

    Another benefit is that when you combine a fixed dose combination with two or three actives, you can basically reduce the side effects. Additionally, the cost of a FDC normally is much lower than if you were producing in three separate products with three separate manufacturing and testing costs. By combining it into one, the cost is a huge benefit for pharmaceutical companies.

    From a patient’s point of view, copays are much less because instead of paying two or three copays, you’re only paying one. Also, from a convenience point of view, you only have to take one tablet instead of two or three different ones.

    Lee Karras: Another huge benefit is that FDC development typically goes by the 505(b)(2) regulatory route, which is an NDA, but is typically not as high as a barrier for approval as a new molecule. So, it’s a way for a company to get access to proprietary NDA market level pricing, but not have the risk of hundreds of millions of dollars in new chemical entity drug development.

    CP: How has the market for FDCs grown over the years?
    Qu:
    From 1990 through 2013, the FDA approved 131 FDC products, which is about 5.7 per year. Of those 131 approved FDCs, 98 were oral dosage forms. Between 2010 and the end of 2015, of the 655 New Drug Applications (NDAs) approved by the FDA, 63 were for FDCs. That accounts for about 10% of the NDAs approved during that 5-year period and, on average, 12.6 new FDC products per year. This shows us that the market for FDCs has grown and is continuing to grow.1

    Karras: A lot of pharma companies, such as Gilead and Merck, have combined what were once single pill, single tablet, or single capsule products and combined them into a multi-API product. When we talk about market size, we’re shifting away from single-entity market to multi-entity market size and these branded products are multi-billion-dollar products now. The revenue growth is substantial.

    CP: From a developmental point of view, what are the biggest challenges for FDC’s?
    Qu:
    One of the biggest challenges is combining two or three tablets together successfully. Sometimes, for example, combining an immediate release drug with an extended release drug can be difficult. If the APIs are not compatible, you’ll have to try to separate them within the tablet. Another challenge is choosing the right technology and format, and there are three that you can choose from. One is making a mono-tablet if the APIs are indeed compatible. If not, you can make a bilayer tablet, which has one API per layer. The third option is a mini-tablet. They have many benefits and they can be put into capsules, as well as other forms such as stickpack.

    Karras: API to API interactions is a critical challenge. In addition, there are complexities and challenges on the analytical side, because now you have two or three APIs that each have their own impurities. You’ll have to come up with analytical tools to determine the relative impurities for each API, and the combined interaction that results from those API’s and impurities. So, the analytical aspect of the development is also important.

    CP: What is the importance of taste masking?
    Qu:
    Taste masking is especially important for pediatric formulations because a lot of kids won’t take their medicine if they don’t like the taste of it. In addition, taste masking can be used for API which has bitter taste. The traditional way is to use a testing committee panel, where a panel will test assorted flavors. But now, electronic tongues have been introduced. The machine will help determine what the majority of people will like or not. Furthermore, taste masking can be achieved by different formulation technologies such as, ion exchange, polymer coating and hot melt extrusion etc.

    Karras: The core of taste masking is really around pediatrics. Removing the bitterness of formulations is important. Typically, more on the oral solution side, but on the tablet side it must be considered as well. What’s done typically is utilizing a coating on the tablet that makes it easier to swallow. But on the oral solution side, typically flavoring and using a sweetener is done to facilitate patient compliance and mask taste.

    CP: What indications and areas are major market drivers for FDC drugs?
    Qu:
    I would say that there are 3 major areas that are driving the FDC market. One area is HIV/AIDS, a lot of FDCs are used there. Another area is diabetes. Most diabetes drugs are using two or three APIs in one tablet. Another area is hypertension.

    Karras: The anti-infective area is a big area for FDCs. Back in the initial stages of AIDS therapy, there was a multi tablet cocktail where patients were taking sometimes up to 10 tablets. Now, with FDCs, that’s reduced to 1 or 2 tablets. Each of those contain multiple APIs that do the same thing as the multiple tablets used to. Another example is with the diabetic population. A large part of that population consists of individuals who have high blood pressure, combined with arterial sclerosis, combined with several other conditions. Therefore, if we can put some products together, we can solve multiple issues for many people with one drug.

    CP: Are there any indications you think we will see using FDCs more moving forward?
    Karras:
    I think we’re going to see it emerge more in the pain area with the opioid epidemic going on. I think you’re going to start seeing many more combinations in that category that consist of opioids and opioid antagonists, so that you get the pain relief, but you won’t get the addictive high or other effects that results from being on opioids for the long-term.

    Qu: Another area I think will see growth is in cancer treatment. Often, doctors give their cancer patients drug cocktails. Those drugs have the potential to be consolidated into FDCs, and that area has the potential to see growth once those APIs can be successfully consolidated.

    CP: What is the significance of partnering with the right CDMO?
    Karras:
    One of the important reasons when partnering with a CDMO is that the APIs and fixed dose combination oral solid dose products are sometimes manufactured in an unconventional way therefore experience is critical. You don’t just blend materials and compress them into tablets or put them into capsules. There are typically unit operations that are needed to ensure that the clinical profile is met. This means you need a CDMO that understands many different process trains, has many different capabilities, and has beyond small-scale capacity so that you can scale it up and be commercially viable from a cost of goods perspective. Having a CDMO that just has one blender and one tablet press will not work for a FDC product.

    Halo can cover everything from granulation, to roller compaction, to mini tablet and bilayer tablet manufacturing. We have every process train covered for really any combination that you can think of. I think beyond that, understanding the analytical side and how to come up with an appropriate analytical method to test is also critical. There are some CDMOs that are just formulators and don’t have analytical expertise, and when this happens, we’ve had to go through and rework the entire analytical suite to ensure that the product is acceptable.

    Qu: Like Lee mentioned, a CDMO must have the technology options to be a successful FDC production partner and the CDMO must be experienced and be able to be a one-stop-shop for both pediatric and adult formulations. 

    References
    1. Kyu Chan Kwon and Chulung Lee, “ 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” Therapeutic Innovation & Regulatory Science. Vol 51, No. 1 Pages 111-117.
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