An increasing number of biosimilars have been approved in the United States, but many clinicians are still poorly informed about what constitutes a biosimilar, and what is involved in their unique pathway to approval, said Andrew D. Zelenetz, MD, PhD, Medical Oncologist, Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York City. He discussed this topic at the NCCN 2019 Hematologic Malignancies meeting.
Biologics are complex, but key, components of modern medicine, particularly in oncology, but the biosimilar pathway establishes a safe and effective means of proving biosimilarity while ensuring competition among biologic drugs.
“If we’re going to make room for new innovations, we have to pay a little bit less [for these drugs] than we have been for the last 20 years,” Dr Zelenetz said.
The list of FDA-approved biosimilars continues to grow in oncology and supportive care, and oncology providers should be informed about these important drugs.
What Is a Biosimilar?
Biosimilars are drugs that have been shown to be highly similar to a reference (or innovator) biologic agent, based on appropriate nonclinical and clinical studies.
“The biosimilar pathway is an abbreviated pathway for things that are truly biosimilar,” Dr Zelenetz explained.
There are tight regulations about how much a molecule can “drift,” but it is important to understand that biologic molecules are always biosimilars of themselves. Biosimilars undergo exhaustive physiochemical, functional, and immunogenicity assessments to establish “fingerprint-like similarity” to the reference drug. “Even the impurities have to be the same,” he added. “I know that sounds weird, but it’s true.”
Most important, the clinical efficacy and safety of the biologic molecule must have been demonstrated by the reference drug (ie, the innovator drug), and the biosimilar must not be different from the innovator drug in a clinically meaningful way.
“So it’s not that the biosimilar has to recreate the wheel,” Dr Zelenetz said. “If you had to recreate the wheel, there would be no advantage and no reason to make a biosimilar.”
For example, he said, duplicating every single clinical trial done with rituximab (Rituxan) between 1997 and today would never be cost-effective. So when a biosimilar is approved by the FDA, there should not be an expectation that there will be differences in safety and efficacy compared with the reference agent.
The Role of Extrapolation in Biosimilar Development
Extrapolation—the expansion of use to other approved indications based on clinical and safety data from 1 indication—is a key concept in the development of biosimilars. This process, which can provide substantial savings in drug development, requires that biosimilars meet certain criteria so that the mechanism of action of the drug, the pharmacokinetics, the pharmacodynamics, and the immunogenicity must all be the same from one indication to another.
“So if you have a biologic that meets these requirements, you should be able to extrapolate from one indication to another,” Dr Zelenetz said.
For example, data from a clinical trial of trastuzumab (Herceptin, a HER2/neu receptor antagonist) in the setting of HER2-overexpressing metastatic breast cancer could reasonably be applied to the adjuvant setting, or even to the treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma. This is because the mechanism of action, pharmacokinetics, pharmacodynamics, and immunogenicity do not differ between indications.
However, although a clinical trial of rituximab versus biosimilar rituximab in rheumatoid arthritis demonstrated virtually identical results, leading to the FDA’s approval of the biosimilar candidate for that indication, these data could not reasonably be extrapolated to the lymphoma setting.
A study of the biosimilar rituximab-abbs (Truxima) versus its reference rituximab would have to be carried out in the lymphoma setting to obtain biosimilar approval for that indication.
“The study needs to be in a suitably sensitive population, and in my opinion, the most sensitive indication would be single-agent rituximab in untreated follicular lymphoma,” he said. “Several of the biosimilars have used that exact study design, because it is in fact highly sensitive.” Based on highly similar outcomes from the study comparing the 2 agents, rituximab-abbs was also approved by the FDA (in November 2018) for patients with untreated, advanced-stage follicular lymphoma.
This biosimilar approval was restricted to this specific indication, but Dr Zelenetz argues that rituximab-abbs should be extrapolated to the treatment of other types of lymphoma.
“Even though the approval was restricted, there are no data suggesting that they shouldn’t have gotten full extrapolation. I suspect it was because the sample size of the study was relatively limited, and the FDA was being conservative,” he suggested.
Extrapolation should only be considered for indications where the mechanism of action is identical to that studied in the pivotal trial. In the absence of sound justification for extrapolation, additional clinical trials are necessary.
According to Dr Zelenetz, clinicians generally want certain findings established before they are comfortable with extrapolation, including similar clinical efficacy and time-to-event end points.
“And we’d like to see truly sensitive indications be tested for the evaluation of these drugs, so we know that the effect is really related to the drug that we’re studying,” he said.
It is also important to realize that the standards for “interchangeability” are different and more stringent than for biosimilarity. The safety standards for determining interchangeability between biosimilars and reference drugs require that the biosimilar produces the same clinical result as the reference in any given patient, and the risk of safety or diminished efficacy because of alternating or switching between the biosimilar and the reference product is no more than using the reference drug without switching.
“No drug yet has been approved as interchangeable,” Dr Zelenetz said. “It is a higher standard than biosimilarity.”
What’s in a Name?
When first deciding what to name biosimilars, some argued that using the same name for an innovator drug and its biosimilar would make it too difficult to trace any rare adverse events that arise, although it would communicate that these agents are “highly similar.” Using different names would clearly distinguish the biosimilar from the reference drug, but this may cause confusion about whether the agents are “highly similar,” and could impede adoption and substitution.
The FDA’s solution was to use the originator name, followed by a suffix containing 4 random letters, such as rituximab-abbs or filgrastim-aafi (Nivestym), a biosimilar to Neupogen approved in June 2018. Currently, all biologic drugs, including all innovator molecules, are assigned these 4-letter suffixes. For example, although rituximab is the innovator drug, if it were developed and approved today for the first time, it would have carried a random 4-letter suffix after its name.