Biosimilars: Approval on the Horizon

How these “highly similar” drugs may affect procedure, treatment, and cost

By Katrina A. Wells
Reviewed by Jack Burks, MD
Edited by Susan Wells Courtney

Very likely, the FDA will soon decide on the status of the first alternative “biologic” drugs to challenge the branded disease-modifying therapies (DMTs) presently in use by individuals with multiple sclerosis (MS). Several of the current DMTs approved by the United States Food and Drug Administration (FDA) are “biologics,” which means that the active ingredient for each of these drugs is derived from living cells.

The biologic DMTs for MS include Avonex®, Betaseron®, and Rebif® – three beta interferons that were among the earliest long-term treatments approved for MS, plus Extavia®, a later-approved beta interferon that is the same drug as Betaseron. Tysabri® (natalizumab) and Novantrone® (mitoxantrone) are also biologics.

Copaxone® (glatiramer acetate) and the three oral DMTs, Gilenya® (fingolimod), Aubagio® (oral teriflunomide), and Tecfidera™ (dimethyl fumarate), are not biologics. However, the FDA is currently reviewing alternative drugs similar to Copaxone. Even though it is not a biologic, it has a very complex molecular structure that is difficult to replicate.

In the near future, some of these biologic medications that play a primary role in many treatment regimens for people with MS, will no longer be protected by their original 12-year exclusivity period, thus opening the market to competitors. When ready, these competitors will be able to submit a biologics license application (BLA) to the FDA, possibly bringing less-expensive drug alternatives to the MS community.

The process of exclusivity and subsequent competition was put into place by the Drug Price Competition and Patent Term Restoration Act — or Hatch-Waxman Act — in the 1980s. These acts were passed in hopes of accomplishing two important objectives: (1) to encourage research by large pharmaceutical companies, by allowing them that period of exclusivity to see a return on their investment required for the initial development of complex drugs; and (2) to lower overall healthcare costs through competition among newly introduced drugs. Today, the Patient Protection and Affordable Care Act includes similar provisions under the Biologics Price Competition and Innovation Act (BPCI Act), opening the market to the types of medications that MS patients often use: biologics.

Many individuals are familiar with this idea when discussing generic versions of traditional medications, such as Tylenol® versus acetaminophen. However, biologics and their new counterparts, biosimilars, pose unique challenges due to their complex nature.

The Science behind a Biosimilar

In order to bring a biosimilar to market, manufacturers will need to follow specific guidelines set by the FDA before submitting an application. It must include clinical data showing that the product is of the same efficacy (effectiveness), along with the same safety and purity, as the original biologic, making it “highly similar” to the original, with “no clinically meaningful difference.” This is why the term “biosimilar” is used.

The manufacturer must demonstrate through analysis of the drug and clinical studies that the biosimilar uses the same mechanism of action for the same condition as the original biologic drug. In other words, the biosimilar drug must work the same way within the body, to fight the same disease, as the originally approved medication.

“Currently, at a minimum, as a scientific matter, we expect that there will be a comparative clinical study that is done at least to evaluate pharmacokinetics and possibly pharmacodynamics, if there is a relevant marker,” Leah Christl, MD, the FDA expert on biosimilars, said in an interview with MSAA.

For anyone not familiar with these terms, pharmacokinetics is “the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body,” and pharmacodynamics is “the study of the action or
effects of drugs on living organisms.”1

Roughly translated, although the biosimilar drug and the original biologic drug cannot be identical in make-up, due to their creation in a living cell, they must have the same effect in the end. Readers should note that inactive ingredients can differ between the original biologic drug and the biosimilar as well.

The manufacturer is also responsible for showing how its drug delivery is comparable to the original. Drug delivery refers to how the drug is administered, i.e., if it is given orally, via injection, via intravenous (IV) infusion, or via other methods. Manufacturers may be allowed to make some changes in the delivery device, but they must not interfere with its efficacy.

“Ultimately, a biosimilar sponsor would not only need to provide support for biosimilarity, but they would also have to provide data to support presentation in terms of functionality and patient usability,” Dr. Christl said. This means that the drug must be equal in terms of effectiveness and safety, as well as offer a similar degree of ease of administration. The sponsor needs to ensure that their delivery device is compatible with the proposed product. This ensures that a patient may be able to take the medication with a similar amount of comfort and convenience as the original biologic drug, and be equally inclined to adhere to the treatment schedule.

Bringing Biosimilars to Market

The idea of approving biosimilars is relatively new, especially to the American market. In 2005, the European Union implemented its pathway (approval process) for biosimilars and has since approved more than 10 of these drugs. The United States did not pass its act until 2010 and has yet to approve a biosimilar for public use.

Dr. Christl said the FDA has observed the process in Europe and there is a cooperative working group in which the FDA works with the European Medical Agency (EMA) and Health Canada.

“The purpose of that group is to promote global development of biosimilars and identify emerging issues,” Dr. Christl said. She explained that this group has regular and as-needed meetings to best address concerns among their experts and prepare educational communications to prescribing physicians and patients.

This new field of drug development is not only extremely complex, but is also quickly growing. Dr. Christl explained that the FDA has already seen the demand for biosimilar regulation steadily increase. The FDA expects further increases as the exclusivity period expires for more and more biologics, for which competing companies will want to develop biosimilars, each requiring stringent regulation.

To date, four draft guidances, one procedural and three scientific, have gone through the public-comment process and are in the process of being finalized. Guidances are documents that are provided by the FDA to answer common questions regarding the approval process for a new drug, medical device, or procedure. When in draft form, the document is distributed for comment before it is finalized.

According to the FDA’s website, “FDA guidances contain science-based recommendations that help eliminate uncertainty about what FDA will accept as valid evidence of product safety, product efficacy, and manufacturing quality.” For more information on FDA guidances or any topic mentioned in this article, readers may visit and enter the topic in the site-search area.
FDA officials said that another five guidances are targeted to be drafted in 2014, including one on considerations in demonstrating interchangeability. Interchangeability creates a unique situation in which the FDA deems a biosimilar to be eligible to be substituted for an existing biologic, with the intention that it “can be expected to produce the same clinical result as the reference product in any given patient,” according to the FDA’s website.

Patient Awareness

One of the items the FDA has gleaned from Europe’s experience is the need for prospective patient and prescriber education, according to Dr. Christl. She explained that individuals should actively engage with their doctors and discuss all options available to them, but they can also access webinars produced by the FDA for consumers to better understand biologics and biosimilars as a whole. To access these webinars, readers may go to for part 1 and for part 2. After learning about biosimilars, members of the MS community can integrate themselves into the overall process via patient networks, clinical trials, and the public-comment time period. The public-comment time period enables people to take part in the ongoing process of creating pathways for drug approval.

“We rely on the FDA, their judgment, and their analysis of the situation to assure us that the drugs are as effective and safe as the original drugs. We also rely on the FDA to ensure that the biosimilars are as pure as the original drugs,” Jack S. Burks, MD, chief medical officer for MSAA, said.

But were he to discuss biosimilars with his patients, Dr. Burks said he would want to know and want his patients to know that the studies met the endpoints for safety, purity, and efficacy. A major concern for Dr. Burks and other physicians is the reality of a biosimilar being approved as interchangeable with the original biologic. He asks if a drug derived from different living cells can truly be interchangeable.

THE BIOSIMILARS GUIDE: A Quick Reference for Readers

BIOLOGIC: Biologics are drugs that are derived from a biological source (blood products, proteins, antibodies, etc.) and mimic pathways within our own bodies. These are different from many of the common drugs people use each day that are created in a lab from chemicals. In the MS community, biologics include: Avonex, Betaseron, Extavia, Rebif, Novantrone, and Tysabri.

BIOSIMILAR: Once a biologic drug’s exclusivity period has expired, other drug companies may compete with the original drug by developing a “biosimilar” drug. This term refers to a biological product that is highly similar to the original (reference) biological product, despite minor differences in clinically inactive components, AND, no clinically meaningful differences can exist between the biological product that is highly similar and the original (reference) product in terms of safety, purity, and potency of the product. The standards of both “highly similar” and “no clinically meaningful differences” must both be met for a drug to be a biosimilar of another drug.

Since the active ingredient for biologic drugs is derived from living cells, biosimilar versions of these drugs will not contain the identical molecules. For this reason, biosimilar drugs must meet the two standards mentioned above before they may be considered for approval. Generic versions of the traditional, nonbiologics drugs can be identical in terms of chemical combinations, because they are not derived from living cells, which contain their own unique molecules.

EXCLUSIVITY PERIOD: When a biologic is approved by the FDA, it holds market exclusivity for 12 years (plus an extra six months for any pediatric medications), meaning that competitors cannot enter the market during that time period. In theory, this allows the original developers to recoup their investment and gives incentive for research and development of new biologics. After 12 years, the exclusivity period expires and biosimilars to the original drug can be approved.

GUIDANCE: Just as it sounds, these documents put forth by the FDA will guide manufacturers in their submission of biosimilars for approval. They explain the procedure and the data required and, before finalization, go through a period of public comment in which manufacturers, physicians, patients, and other key stakeholders can give input and request clarification.

INTERCHANGEABLE: This designation, if given to a biosimilar, would be similar to a generic drug in that this biosimilar could be substituted exactly for its biologic (original) reference drug. This would also mean it could be substituted without direction from the healthcare provider who prescribed the original medication.

“The material they’re made from cannot be the same,” Dr. Burks explained. So knowing it will work in exactly the same manner is a difficult concept to pinpoint.

Still, the FDA has those definitions and requirements in place because, Dr. Christl said, “The FDA fully expects interchangeables to be licensed in the future.”

She explained that the FDA has laid a foundation in comparative analytics and comprehensive comparison. These comparisons will identify where differences, if any, may be found in the structure and function of the biosimilar drug. They will then go through a risk-based assessment to look at any impact that these differences might have on safety and efficacy.

As these competitive biosimilar drugs make their way through the approval process, members of the MS community should be aware of when an interchangeable biosimilar is approved and becomes available in the marketplace. As Dr. Burks suggested, patients need to weigh personal risks and comfort level before accepting a substitution for a medication that for many years, has been providing successful treatment for them.

Future Considerations

Eventually, the other factor that physicians and individuals with MS will need to weigh will be cost. The FDA does not consider cost in their evaluation or approval of biosimilars, Dr. Christl said, but with the act named Biologics Price Competition and Innovation Act, price seems an inherent part of the plan.

In the act, it states that the goal is “balancing innovation and consumer interests” by pursuing this pathway of approvals and introducing competition to the biologics market. With the costs of branded medications continually increasing, the hope is that biosimilars will be less expensive to develop and less costly to produce, eventually passing those savings on to consumers.

Cost savings may not be an easy goal to reach. In a 2011 study looking at the European biosimilar market, a researcher suggested that despite the agency’s attempt to create a more cost-effective treatment environment, a long-term impact on price remained to be seen.

“Given that there may be uncertainty surrounding the long-term safety and effectiveness of a biosimilar, the cost-effectiveness of a biosimilar needs to be calculated at multiple time points throughout the life cycle of the product,” the author concluded.2

And like that researcher, patients in the MS community will need to maintain vigilance over the biosimilars market as it applies to them individually and as a community. People will need to know the options as these biosimilars are approved and have their own cost-benefit conversations with their physician. If an interchangeable is approved, people must realize that it could potentially be substituted by a pharmacist without approval from their physician.

As with many processes leading to drug approval, the development of biosimilars will have its hurdles that will affect government decisions. The development of biosimilars will also impact patients, who will need to keep aware of these competitive biosimilar medications as they monitor their own treatment options.

1 The American Heritage® Medical Dictionary, Copyright ® 2007, 2004 by Houghton Mifflin Company.

2 Simoens S. Clinicoecon Outcomes Res. 2011; doi: 10.2147/CEOR.S12494.