This past year, the FDA approved three biosimilars for use in rheumatology. A biosimilar to Remicade, called Inflectra, launched in late November 2016. As the next few years will see changes to the availability of biosimilar treatments, the following article addresses some basic questions that the introduction of these drugs raise: What is a biosimilar? Are they as effective as the reference product? Do they carry the same risks? And how much cheaper will they be?
What is a biosimilar?
It is important first to understand what a biologic is in order to understand biosimilars and why they are not the simple equivalent of generics. "Biological products," according to the FDA, "include a wide range of products such as vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins. Biologics can be composed of sugars, proteins, or nucleic acids or complex combinations of these substances, or may be living entities such as cells and tissues." In the modern world of DNA technology, "Biologics are isolated from a variety of natural sources - human, animal, or microorganism."
For rheumatoid arthritis, biologics include the drugs Orencia, Humira, Kineret, Cimzia, Enbrel, Erelzi, Simponi Aria, Remicade, Rituxan, Actemra, and arguably Xeljanz (synthetic). The first biologic treatment option, Enbrel, appeared in 1998. The molecular structure and targeted pathway of inflammation can differ between these drugs. Tumor necrosis factor, Interleukin-6, B-Cells, T-Cells, and Interleukin-1 are the antibodies or cells that these drugs block, inhibit, or act on to reduce or stop the inflammatory response characteristic of RA.
Unlike traditional drugs that are chemically synthesized by combining ingredients, biologics are complex molecules manufactured through living cells. A traditional drug can be analyzed in the lab to discover its chemical components. In contrast, for a biologic, "it is difficult or even impossible to break down the components."
A generic chemical drug is going to have the same active ingredient, strength, and dosage as the original drug. A biosimilar is not the same things as generic in this regard, as the molecules will be similar but not identical to the parent drug. "Biologics manufacturers must ensure that the manufacturing process remains the same over time by tightly controlling the source and nature of starting materials and consistently employing hundreds of process controls that guarantee predictable results." A biosimilar requires a new manufacturing process and may result in a slightly different molecular product. The FDA, for this reason, had to come up with unique guidelines for the approval of biosimilars.
In sum, a biosimilar is as alike to the original product as possible, but is not an exact replica. "The FDA considers a product to be “biosimilar” to a reference product if it is shown to have no clinically meaningful differences with respect to safety, potency and purity."
Are biosimilars as effective as the reference product?
In order to gain FDA approval, they must be. "In order to obtain approval for a biosimilar, the manufacturer must submit an application showing data from analytical studies, animal studies and clinical studies assessing immunogenicity, pharmacokinetics and pharmacodynamics. At least one randomized clinical trial (RCT) is typically required to demonstrate that the efficacy, immunogenicity and safety of the biosimilar are comparable to its reference product." Clinical data from 600 RA and AS (Ankylosing Spondylitis) patients substantiated the approval of Inflectra.
What about safety?
As stated above, the safety must be comparable to the reference product for approval. Additionally, in the case of Inflectra, large-scale tests in Europe on the safety of switching from Remicade to the biosimilar have been performed. Importantly, in a double blind trial of 481 patients with specified rheumatic conditions lasting 52 weeks, switching from Remicade to the biosimilar "was not associated with an increased risk of adverse events." In summary, safety and risk of biosimilars should be homologous to the reference product. Post-marketing surveillance will also be carried out.
What is the cost difference?
Inflectra is priced at a 15% discount to Remicade at wholesale. This does not include rebates to insurers or discounted startup plans for new patients. According to Fortune.com, "the 15% reduction isn't anywhere near the savings biosimilars provide in other countries, where they have been available for nearly a decade. For instance, Remicade biosimilars have been sold at 45% and even higher discounts compared to the original drug." Pfizer, the manufacture of Inflectra, defends its pricing due to differences in markets, regulations, and systems of care between Europe and the U.S.
Biosimilars of Humira and Enbrel also received FDA approval in 2016, and will enter the market in the coming years. It is hoped that increased competition will lower out of pocket costs for patients.
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