What are Biosimilars?

“There are many … structural and functional differences that can emerge when you go from the original biologic to a biosimilar.”

—Gary H. Lyman, MD, MPH

Defining the Category

In the simplest terms, a biosimilar is a biologic product that is similar (but not identical) to a biologic product already approved by the U.S. Food and Drug Administration (FDA). How the products are developed and how they enter the marketplace is a bit more complicated.

But what are biologics? These drugs are developed from living organisms, whether human, animal, or microorganism cells.² They cannot be made through synthetic chemical processes, unlike traditional medications. Biologic products also are distinctive because they can be made of sugars, proteins, nucleic acids, or complex combinations of these substances, or they may be living entities such as cells and tissues.³

“These products are grown in living systems and usually in cells,” explained Gary H. Lyman, MD, MPH, professor of medicine at the University of Washington and co-director of the Hutchinson Institute for Cancer Outcomes Research at the Fred Hutchinson Cancer Research Center in Seattle, Washington. “We can clone the gene and ensure that the protein that is produced has the same amino acid sequence, but there are many other structural and functional differences that can emerge when you go from the original biologic to a biosimilar.”

Generics Versus Biosimilars

Although each drug class carries distinctive characteristics, generic and biosimilar medications share the same goal: to provide patients with less-costly treatment options that offer the same clinical benefits as more expensive brand-name or biologic medications.

“Generic products are simple molecules, while biosimilars are large proteins or macromolecules, so they are different in their structure and how they are produced,” Brandon Shank, PharmD, MPH, a clinical pharmacy specialist at the University of Texas MD Anderson Cancer Center in Texas, told ASH Clinical News.

The divergence starts with the manufacturing process. Generic products are identical copies of branded drugs; they can be reproduced easily by assessment of the pharmacokinetics and dynamics of an FDA-approved drug and production of a similar chemical formulation that uses the same active ingredients. Generics are also approved with the same strength, indication, form, and route of administration as branded products, and they must be manufactured under the same strict standards.

Unlike generics, biologics are not identical copies of their reference products. Instead, the FDA mandates that there are “no clinically meaningful differences in terms of safety and effectiveness from the reference product,” as well as only minor differences in the clinically inactive components.²

“Depending on which drug is being reworked, the manufacturing process can be really complicated,” Dr. Shank said, adding that, due to their makeup, biosimilars may need to be grown in a live model or need a specific enzymatic reaction with a protein and bacteria. Companies that are accustomed to making generic products would need to vastly alter their facilities to be able to effectively manufacture biosimilar products.

Receiving Approval

Biosimilars face different regulatory hurdles than biologic products or generic drugs. The approval of biosimilars is outlined in the Biologics Price Competition and Innovation Act of 2009.⁴ The legislation accelerates biosimilar approvals by creating an abbreviated approval pathway that requires a less substantial data package submission.

Approval of a traditional oncology biologic requires submission of a biologic license application and a standard approval process that includes lab work and analytics.

Most of the traditional approval deliberations are “heavily weighted on pivotal clinical trials data,” noted Robert M. Rifkin, MD, medical director of biosimilars for McKesson Specialty Health-U.S. Oncology Network. The approval process for biosimilars, on the other hand, relies more on analytics and biosimilarity exercises outlined by the FDA. “Basically, this means starting by reverse-engineering a biosimilar to the originator,” he said, adding that some submissions include as many as 40 analytics to show that a biosimilar is highly similar to its reference product.

Data are evaluated at each step of analysis to influence subsequent steps, and they are used to provide extensive, head-to-head comparisons of the biosimilar and reference product at many levels, including:⁵

• structure and function (the foundation of biosimilarity)
• pharmacokinetics and pharmacodynamics
• safety and efficacy
• immunogenicity

The biosimilars license application requires supporting clinical material, but the results of structural and analytic testing are better able to detect differences in agents’ pharmacokinetics, potency, and purity than traditional phased clinical trials. Taken together, these data form the “totality of evidence” that the FDA examines when considering approval of a biosimilar.

Once the FDA is satisfied that the evidence is both substantial and sensitive enough to detect potential differences and to address residual uncertainty that may exist, the agency can approve the biosimilar.

“If there are 10 biosimilars for one product and each insurance company requires a separate, specific biosimilar, it will be quite complex for a provider to adhere to or for a pharmacy to manage.”

—Brandon Shank, PharmD, MPH

Interchangeability and Extrapolation

In the survey referenced earlier, nearly 60 percent of respondents correctly understood the requirements a biosimilar must meet to be approved as “interchangeable” (i.e., must be shown to be safe and effective for back-and-forth switching with no negative impacts to safety or efficacy), fewer people correctly understood what the term “interchangeable” meant in the context of biosimilars.

Some believe that this term refers to the ability to do a therapeutic exchange with the originator biologic product, as would be decided by a Pharmacy and Therapeutics Committee, Dr. Rifkin explained. However, interchangeability is a regulatory term that allows for pharmacy-level substitution without the intervention of the physician who originally prescribed the reference product.

To be granted interchangeability, biosimilars must go through a separate, more rigorous approval process. And, to date, no biosimilars have been granted such status.

“Extrapolation” is another fundamental premise of biosimilars about which many are unfamiliar.¹ Extrapolation is the process by which a biosimilar may be approved for one or more indications for which its reference biologic product is licensed, but for which there was no head-to-head clinical comparison. This process relies on the totality of evidence obtained in the initial stages of FDA review, and every indication for which extrapolation is sought must be scientifically justified.

For example, when filgrastim-sndz was the first biosimilar to be approved in the U.S. in March 2015, it was indicated to reduce the risk of febrile neutropenia in patients receiving myelosuppressive chemotherapy.⁶ After earning approval for that indication, it was later granted approval for all other indications for which its reference product was approved – without submission of separate clinical data for the other indications.

“Extrapolation is an issue that has and probably will continue to concern hematologists,” Dr. Lyman said. However, he added, “if we required the same amount of both preclinical and clinical data for the biosimilar that we require for the reference product, we [would] undercut one of the motivations for developing biosimilars: reducing development costs and increasing competition in the marketplace.”

“Although the FDA indication may be broad, I am not as confident that you can extrapolate all indications, especially if the dose changes, because there may not be a linear dose relationship,” Dr. Shank reasoned. Rather than awarding extra indications without extra clinical evaluations, he would prefer to review the patient population included in the study that used a biologic, then evaluate the biosimilar in that same patient population before slowly advancing it out to other patients.

The concerns over extrapolation expose other concerns about the safety of biosimilar products, particularly because biosimilars do differ slightly from their reference products. There is also a lack of clinical data in the U.S. to show the safety and efficacy of biosimilars in various patient populations and over time.

Prescribing Biosimilars

Biosimilar approval has focused primarily on the supportive care aspects of oncology, such as the approval of myeloid growth factors like filgrastim-sndz. However, efforts have recently expanded to cancer treatment. On September 14, 2017, the FDA approved bevacizumab-awwb for the treatment of certain colorectal, lung, brain, kidney, and cervical cancers.⁷

The FDA is also expected to issue its decision on the approval of MYL-1401O, a biosimilar of trastuzumab, which is used to treat breast and gastric cancers, by the end of the year.⁸

As biosimilar approvals for cancer treatment become more prevalent, Dr. Shank said, so does the need for oncologists to educate themselves about what a biosimilar is and how it can be used in everyday practice. For instance, dosing and administration of a biosimilar may differ from its reference product.

“Health-care professionals will need to learn the differences in administration, preparation, and procedures,” he said. “If there are 10 biosimilars for one product and each insurance company requires a separate, specific biosimilar, it will be quite complex for a provider to adhere to or for a pharmacy to manage.”

Regulations stipulate that biosimilars can be used for newly diagnosed patients or those who have already received the reference product. Physicians must write the specific name of the biosimilar on the prescription order when prescribing such medications. Pharmacists can only dispense the specified biologic, unless they receive approval from the prescribing physician to make a substitution.

Interchangeable biosimilars are the sole exception to this rule, but the concept doesn’t sit well with some physicians. Dr. Lyman noted that 35 states have drafted legislation that would require a pharmacist to alert a physician about any change.

International Reputation

Biosimilars are now starting to enter U.S. clinical practices, but many physicians are reluctant to prescribe them. For a glimpse into the future of biosimilars, clinicians can look to Spain, Canada, Australia, Japan, and other countries where biosimilars have taken hold.

“In the beginning, there was a lot of lack of education, and people confused biosimilars with generics, which have very poor press,” said Pere Gascón, MD, PhD, senior consultant and chairman of the oncology program at the Hospital Clinic of Barcelona, of the initial reception in Europe. “It was difficult to convince physicians to switch to biosimilars because of the bad reputation of generics.”

However, after a decade of educational efforts, Dr. Gascón has seen physicians’ comfort levels grow substantially. “It was a progression,” he said. “Right now, I would say biosimilars are widely accepted in Europe.”

The uptake could also be attributed to Europe’s more extensive biosimilar approval processes, which may help allay health-care providers’ concerns about safety and efficacy. “There is no accelerated approval pathway for biosimilars through the European Medicines Agency,” Dr. Gascón explained. “The process takes basically the same amount of time as the originator product.”

In the U.S., insurance companies are likely to drive the acceptance and use of biosimilars, Dr. Lyman noted. “Clinicians may be concerned that their control or ability to choose among these products – or to choose the brand name that they have grown comfortable with over the years – will be usurped by health systems and insurers, who will require that they use the new biosimilar if it’s less expensive,” Dr. Lyman said.

Regardless of physician attitudes toward biosimilars, one thing is certain: “Biosimilars are coming,” Dr. Rifkin promised, “and physicians need to be familiar with them.” —By Jill Sederstrom