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Biosimilars Are Not Generics
Biosimilar drugs have arrived. They are not generics. Do you know the difference?
On March 6, the FDA approved the first U.S. biosimilar, Zarxio (filgrastim-sndz), which will be manufactured by Sandoz, a Novartis company. Zarxio is biosimilar to Amgen’s Neupogen (filgrastim).
Biologic drugs make up an ever increasing share of the drug market. The category includes agents such as Herceptin (trastuzumab, Genentech), Humira (adalimumab, AbbVie), Avastin (bevacizumab, Genentech) and insulin. Biologics can be expensive. Trastuzumab can cost more than $35,000 to treat a patient with breast cancer. Adalimumab can run more than $50,000 per year to treat rheumatoid arthritis. In 2013, 28% of the money spent on drugs was for biologics.
Many biologics are off-patent or are about to be. This presents an opportunity for other companies to enter the marketplace and manufacture biosimilar versions of them. Many physicians incorrectly refer to biosimilars as “generic biologics.” The potential for confusion is great. These agents are not exact copies, as generic drugs are, and thinking of and using them as such could lead to serious medication errors.
Copies, generics, biosimilars
Generics originated in 1984 with passage of the Hatch-Waxman Act. This law applied to small molecular drugs that were chemically synthesized. After an innovator drug lost its patent protection, this law allowed other companies to use an abbreviated approval process to quickly and cheaply bring copies to market. Because generics have the identical active ingredient, there is no need to repeat all of the testing that the innovator company did for initial approval. Thus, these drugs are able to come to the marketplace with savings sometimes as high as 70%, sometimes higher. Availability of generics has improved patient access and saved payers money. Currently, about 85% of prescriptions in the United States are filled with a generic drug.
Biosimilars originated with passage of the Affordable Care Act (ACA) in 2010. Biologic drugs are much larger and more complex molecules than chemically synthesized drugs. For example, aspirin, a chemically synthesized drug, weighs only 180 daltons (d) and has 21 atoms. A biologic, such as immunoglobulin G antibodies, can have more than 20,000 atoms and weigh more than 150,000 d.
Richard O. Dolinar
Producing biologics is extremely expensive. The average cost of bringing a new drug to market was recently determined by Tufts University to be $2.6 billion. Bringing a new biologic to market is usually above the average.
Producing a biologic is much like farming, but at a molecular level. Living material, often in the form of unique cell lines, is used in the production process. Because of their complexity and manufacturing processes that use different living materials, biosimilars are not exact copies, but rather variants of innovator biologics. It is not currently possible to use two different cell lines to produce exactly the same product; thus the term used is biosimilar and not “bioidentical” or generic. In order to address the high cost of biologics, the ACA tasked the FDA with developing an abbreviated approval pathway for biosimilar drugs.
Substitution, notification
From a physician’s perspective, the substitution of biologics and biosimilars is an important issue with clinical implications. Many physicians mistakenly believe that biosimilars are merely “generic biologics” and, thus, could be substituted in place of the brand-name reference drug. In reality, this may not be true.
The ACA established two categories of biosimilar drugs. The first, called simply “biosimilar,” refers to those agents that are highly similar to the reference biologic, and thus when seeking FDA approval for them, manufacturers are able to use information developed by the innovator company. This allows new companies to skip some of the studies the innovator was required to perform, which should save time and money when bringing them to market. However, although FDA-approved for use, these agents will have to meet a higher standard of regulatory scrutiny in order to be approved for substitution. That second category of biosimilars, which are substitutable, will be called “interchangeable biosimilars.” These agents will be expected to have the same effect as the reference biologic.
A patient who is drug-naïve could start with either the brand-name reference biologic or its biosimilar. But for a patient who is already taking the reference drug, a biosimilar drug could not be substituted unless that drug had been determined by the FDA to be an interchangeable biosimilar. The importance of confirming the interchangeability of a biosimilar takes on added significance in the treatment of chronic progressive diseases, such as cancer, rheumatoid arthritis and multiple sclerosis, where ground lost is never to be regained.
How interchangeability will be determined is unclear. What if the agent in question is a lifesaving cancer drug? Will randomized clinical trials be performed with the hope that the biosimilar will prove to be as effective as the original? What if it isn’t? Who would volunteer to be in such a study?
Currently, there are no FDA-approved interchangeable biosimilars. However, will physicians mistakenly think that biosimilars are generics and substitute these drugs inadvertently, not realizing that they are not interchangeable? Will third-party payers or hospitals inappropriately apply pressure to physicians to substitute one for another? Who will decide whether to substitute?
That part of the ACA titled “Biologics Price Competition and Innovation Act” addresses the substitution of a biosimilar for a reference biologic. Section (351)(i)(3) states, “The term ‘interchangeable’ or ‘interchangeability,’ in reference to a biological product that is shown to meet the standards described in subsection (k)(4), means that the biological product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.” The FDA will determine which biosimilars are interchangeable, but each individual state that applies the law will determine what its pharmacists will be allowed to do.
The choice of the phrase “the biological product may be substituted without the intervention of the health care provider” is perplexing. Does this mean that the pharmacist will be able to substitute a biosimilar in the place of the reference biologic without obtaining the permission of or even notifying the prescriber? The states are currently wrestling with this issue.
Implications of naming
It is possible that the debate regarding these drugs and their substitution was over before it even started.
The term biosimilar facilitates those who argue that these drugs are so similar that physician notification should not be required when these drugs are substituted. But what if after the switch the patient is not doing well? How will the prescriber know to switch back to the first drug rather than move on to a second choice?
Instead of calling them biosimilar drugs, perhaps they should be called “biodifferent” drugs. After all, it is not their similarities that need concern us, but rather their potential differences. Would people be so eager to switch these drugs without notifying the prescriber if they were called biodifferent drugs?
Other potential challenges lay ahead for the clinician. One biosimilar might be determined by the FDA to be interchangeable with the reference biologic, while another might be determined to be highly similar but not interchangeable or interchangeable only in two of the five indications of the drug. How will prescribers remember which they are? Or will physicians just consider them to be generics and use them all without any regard to interchangeability? If so, will patients be harmed?
If two drugs are similar, they are not identical. If they are not identical, then they are different.
Biosimilar or biodifferent?
Richard O. Dolinar, MD, is a senior fellow with The Heartland Institute and a clinical endocrinologist specializing in diabetes in Phoenix. He can be reached at rdolinar@heartland.org. Dolinar reports no relevant financial disclosures.