By David Borenstein, MD 9/2019
One way to lower the cost of biologic medications is to create biosimilar drugs that have active properties highly similar to an already FDA-approved biological drug. These “biosimilar” medications are now available in Europe and the US. In 1998, the US Food and Drug Administration (FDA) approved the first therapy that decreased levels of tumor necrosis factor (TNF) in the body. TNF was known to be a cytokine (cell messenger) that perpetuated inflammatory processes associated with a wide range of autoimmune disorders. The first approved anti-TNF therapy was infliximab (Remicade®), a biologic drug, and it was indicated for the treatment of inflammatory bowel disease, like Crohn’s disease and ulcerative colitis. Subsequently, infliximab was indicated for the treatment of other autoimmune disorders, such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), psoriasis and ankylosing spondylitis (AS). A number of other biologic therapies were approved by the FDA for the treatment of autoimmune disease including adalimumab (Humira®), etanercept (Enbrel®), golimumab (Simponi®), abatacept (Orencia®), secukinumab (Cosentyx®), and tocilizumab (Acemtra®), among others. While these agents are very effective in a wide range of disorders, their high cost has been a barrier for many patients.
What is a generic conventional drug and how is the process different for biologics?
Drug therapies for disease come in varying shapes and sizes. Many of the conventional drugs we use consist of a relatively small number of chemicals and are made up of small molecules. A prime example of a small molecule is aspirin, or acetylsalicylic acid or another, acetaminophen.
The lifecycle of a drug starts with an innovative pharmaceutical company producing the original drug through research, testing of the drug through the clinical trials process and eventual approval by the FDA if the drug has demonstrated efficacy and safety. Once a drug is approved by the FDA, a pharmaceutical company acquires patent protection to manufacture and sell that FDA-approved drug for a specified number of years. A pharmaceutical company has 20 years of patent protection on a drug from the time the drug is invented in the research phase. Once the patent-protection ends, competitor companies can produce a copy of that small molecule drug, which is considered a generic form of the drug. A generic form of the drug can easily be made because the structure of small molecule drugs are well defined and manufacturing of the identical copy is predictable, easy to store and relatively stable. Therefore, generics of conventional drugs are relatively easy to manufacture, at a fraction of the cost, and could be sold at a reduced expense compared to the original drug.
Creating a generic drug for biologics like anti-TNF drugs is much more complicated because their structure and mixture of molecules is more difficult to identify or characterize compared to small molecule conventional drugs. Biologics consist of a number of protein strands that take the form of antibodies and are derived from genetically engineered living cells, usually bacteria. 1 Biologics have a sequence of amino acids that form a specific shape that give that protein its ability to decrease disease activity. In addition, other chemicals can be attached to the proteins to maintain its essential shape (glycosalation). If the sequence of the amino acids is incorrect, or if the glycosalation destabilizes the form of the protein, it will not work or be inactive.
What is a biosimilar?
According to the United States FDA, a biosimilar is a biologic that is highly similar to the reference product with no clinically meaningful difference in terms of safety profile, purity, and potency. To understand the role of a biosimilar, an understanding of the approval process for the originator biologic is necessary.
For approval of an originator biologic, the protein needs to be tested in individuals with a specific disease like RA or AS or cancer. The agent needs to be tested against a placebo, and frequently against an already approved treatment with a known outcome. In order to be approved for a disease, the originator has to be tested in that disease. It cannot be assumed that because a biologic works in RA, that it will work equally well in inflammatory bowel disease. Each disease needs its own study. In addition, the originator needs to be studied in regard to safety and toxicity in each disease. The determination of safety is an ongoing process that does not stop when the biologic is FDA approved, but continues in post-approval studies to be sure that long-term use does not increase risk for a toxicity not seen with brief exposure to the agent.
The approval of a biosimilar is different. The biosimilar needs to be physically similar, but not necessarily identical to the originator biologic. It must be tested in animals to be sure there are no unexpected toxicities. The biosimilar is studied in a clinical trial for effectiveness and safety compared to the originator product. If a biosimilar is effective in one disease, RA for example, is it effective in all the diseases that the originator was approved for. That decision involves extrapolation of results.
What is extrapolation?
In order to make the process of approval of biosimilars less expensive, the FDA has decided that a biosimilar may be approved in one or more indications for which the originator product is licensed based on the totality of evidence and scientific justification.3 In this circumstance, the positive results of a RA clinical trial of a biosimilar is extrapolated to be equally effective in other diseases for which that biologic is indicated. For example, if the biosimilar for infliximab is effective in RA and AS, the FDA could approve the drug for psoriasis and inflammatory bowel disease even though those diseases were not studied. Extrapolation is not automatic, but the FDA can give approval for the prior approved indications at its discretion. If the originator biologic and its corresponding biosimilar are approved for the treatment of the same diseases, are they interchangeable? The answer is no.
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What is interchangeability?
Even though the originator biologic and its biosimilar have similar characteristics, they are not interchangeable unless additional studies are completed. Interchangeability refers to the appropriateness of substituting for the original biologic without the intervention of the healthcare provider who prescribed the originator biologic. Interchangeability would allow the insurance plan or specialty pharmacy to substitute the biosimilar for the originator biologic without making the prescribing physician aware that the change had occurred. The requirements for interchangeability are higher than those to achieve biosimilar status. In order to be interchangeable, the biologic must be a biologic, must be able to produce the same clinical results as the reference biologic in any given patient, and not cause any increased harm or diminished efficacy due to alternating or switching between biosimilar and originator biologic than using the originator with no switching.4 In 2017, no biosimilar has been approved by the FDA to be interchangeable with the originator biologic. Since the bar is so high to be approved for interchangeability, it is unlikely that any biosimilar will spend the resources to achieve that designation.
Biosimilars have been approved for rheumatic diseases by the FDA. Although four biosimilars are approved, only Inflectra (infliximab-dyyb) is currently being marketed and available as therapy in the United States. Inflectra has been tested in other countries for effectiveness and safety in RA and AS.5,6 Inflectra was also utilized in a switching study in patients who were stable on the originator biologic, infliximab. Study patients included those with RA, AS, PsA, UC, CD, and plaque psoriasis. At one year, no difference was noted between the originator and biosimilar.7 The study however did not include an adequate number of patients in each disease category to make a definitive statement about individual diseases. Importantly, there was no increase in toxicity associated with the biosimilar. The first biosimilar drug in oncology will be Neupogen/zarxio.
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What is the cost?
Cost is the bottom-line reason for the development of biosimilars. Among the 25 most expensive drugs in 2016, 3 were biologic drugs used for the treatment of rheumatic disorders. The prices of the originator biologics have doubled, at a minimum since their release in 1998. The retail cost is between thirty to forty thousand dollars annually. When biosimilars were allowed in Norway, a 60% savings were gained. It is unclear what the savings will be in the United States, but biosimilars should bring costs down. Initially, Inflectra was priced 30% lower than the originator biologic. Whether those savings will be passed on to the patients remains to be determined.
Many questions remain regarding the use of biosimilars in the United States. Rheumatologists, gastroenterologists, dermatologists, and oncologists remain a bit hesitant in recommending a biosimilar to a patient. Does a patient who is stable on the originator biologic switch to the biosimilar? Is that worth the savings? At what level of savings is the switch worthwhile? Does a patient with an extrapolated disorder wait to choose a biosimilar until a study is published in the United States demonstrating efficacy and safety in their disease? Savings to the patient and society are clearly worthwhile, but only when originator and biosimilar result in the same effectiveness and safety.
FDA Approved Biosimilars For Treatment of Chronic Inflammatory Conditions
RA=rheumatoid arthritis, AS=ankylosing spondylitis, PsA=psoriatic arthritis,
UC=ulcerative colitis, CD=Crohn’s disease, JIA=juvenile idiopathic arthritis
- US FDA: www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cber/ucm133077.htm
- US FDA: www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cber/ucm133077/htm.
- US FDA: ww.fda.gov/Downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf
- Park W, Hrycaj P, Jeka S et al: A randomized double-blind, multicenter, parallel-group, prospective study comparing the pharmacokinetics, safety, and efficacy of CT-P13 and innovator infliximab in patients with ankylosing spondylitis: the PLANETAS study. Ann Rheum Dis 2013;72:1605-1612
- Yoo DH, Hyrcauj P, Miranda P et al: A randomised double-blind, parallel –group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study. Ann Rheum Dis 2013;72:1613-1620
- Jergensen KK, Olsen IC, Goll GL et al: Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomized, double-blind, non-inferiority trial. Lancet 2017KJum10.389(10086):2304-2316