Biosimilars: The Race for Approval

While the scientific advances in the field of biologics move forward, so too does legislation to regulate many aspects of biosimilars and interchangeable biologics, although at a seemingly much slower pace. However, with 21 biologic products (biopharmaceuticals) losing their patent protection by 2019 in the U.S. alone,¹ the race for approval and development is gaining speed.

Sales in biologics, which include vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues and recombinant therapeutic proteins,² make up about a quarter of the $320 billion in drug sales in the U.S. annually,³ and according to the Generic Drug Association, the rising costs of biologics are outpacing any other aspect of healthcare.

Thanks to the Biologics Price Competition and Innovation (BPCI) Act within the Patient Protection and Affordable Care Act, an abbreviated U.S. Food and Drug Administration (FDA) approval process for the licensure of biological products that are demonstrated to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product has been created.⁴ The BPCI Act allows FDA to declare a biosimilar interchangeable provided that it is expected to produce the same results in all patients and, with continued use, the safety and efficacy risks are no greater if a patient were to be switched to a biosimilar than if they had stayed on the innovator drug.¹ FDA defines biosimilars as “highly similar to a U.S.-licensed reference biological product notwithstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.”

While only one biosimilar product has been approved, a few more are under consideration and even more are in development stages. Approvals of biosimilars and subsequent marketplace competition are expected to have a significant impact, much like the approval of generics (a term that applies only to bioequivalents of an already approved small molecule drug), with savings ranging anywhere from $42 billion to $108 billion in the first 10 years alone.⁵

Are Biosimilars Interchangeable?

The fact that biologics are derived from living cells makes them, of course, incredibly complex, and unlike generic drugs, that complexity makes them impossible to replicate. Even nearly imperceptible changes to the cells when making a biosimilar can lead to variances in how a body responds to the drug.

According to the American Society of Health-Systems Pharmacists, infections and immune system disorders are the most common safety problems associated with biopharmaceuticals, although allergy, anaphylaxis and serum sickness are rare because of improvements in purity. Understandably, there is concern about switching from an innovator biopharmaceutical to a biosimilar because the safety profile for the biosimilar will likely be unclear at the time of FDA approval, and any potential adverse events are unlikely to be detected prior to marketing the product. However, the expectation is that most serious adverse events would likely be identified during the testing phase of the innovator product. Even so, due to the nature of biosimilars, any adverse events could differ from those of the innovator drug in clinically significant ways.⁶

Whether a biosimilar can be considered “interchangeable” with a biologic is a question of intense debate and is one factor driving the question of approvals. Kristofer Baumgartner, a spokesperson at FDA’s Center for Drug Evaluation and Research (CDER), says, “There is an additional standard to meet for an interchangeable biological product. In addition to demonstrating biosimilarity, a manufacturer must show that the proposed interchangeable product is expected to produce the same clinical result as the reference product in any given patient. When a product will be administered more than once to an individual (as many biological products are), the manufacturer must also demonstrate that the risk in terms of safety or reduced effectiveness of alternating or switching between use of the proposed interchangeable product and the reference product is not greater than the risk of using the reference product without such alternation or switch.”

Still, Larry Lamotte, vice president of public policy at the Immune Deficiency Foundation (IDF), which serves immunodeficient patients who rely on treatment with the plasma product immune globulin (plasma products are one of the most complex biologics), urges caution: “The one thing we know is minute changes [in biosimilars] from a reference product can create differences in tolerability in patients. Our patients are already at increased risk of everything else in the world, and we would not want them running risks with a new drug. Biosimilars must meet the same safety requirements as their reference product.”

The International Role in Biosimilars

For years, biosimilars have been approved for use in the European Union, Canada, Japan and other countries, but FDA has thus far been slow to respond in kind. FDA is looking at the issue of biosimilars not only in the U.S., but also how they are viewed and used internationally. Baumgartner explains that collaboration via forums with international regulatory colleagues is enabling discussions of potential areas of alignment on scientific approaches to biosimilar development in an effort to support multinational development programs. “For example,” he says, “FDA collaborates with the European Medicines Agency (EMA) and Health Canada to encourage alignment on scientific approaches to biosimilar product development through the EMA-FDA-Health Canada Biosimilar Cluster. Under the Confidentiality Commitments, the regulatory agencies share experiences and best practices to provide biological product developers assurance, when possible, that data developed for one regulatory authority could be acceptable to another regulatory authority. Recently, Japan’s Pharmaceutical and Medical Devices Agency (PMDA) asked to join the cluster. In addition, EMA and FDA can discuss and jointly advise biosimilar applicants on specific development programs through the Parallel Scientific Advice procedure when an applicant makes such a request.”

Several regulatory agencies, including FDA, EMA and PMDA, are involved with the International Pharmaceutical Regulators Forum, chaired by the Korean Ministry of Food and Drug Safety, which has established a working group on biosimilars. The working group’s goal “is to understand the legal requirements and constraints across many regulatory regions and determine the potential for alignment of scientific approaches.”

“It is through these interactions that FDA, EMA and other regulatory agencies are exploring approaches to developing guidance that facilitates multinational development programs for biosimilar products by aligning scientific recommendations and, when possible, leveraging existing data,” says Baumgartner.

There is expected to be high international demand for U.S. biosimilar products once processes have been finalized, approvals have been given and production is underway.

The Notification of Substitution Debate

The BPCI Act did not address notification, and it is an issue that is raising a heated debate. Therefore, due to a concern that the statutes applying to generic drugs may be misapplied to biosimilars that are not identical, some states are already expanding on their laws concerning pharmaceutical substitution. Since late 2013, 23 states have considered legislation that establishes standards for substitution of biosimilar products to replace original biologic products. As of this writing, only eight states have enacted statutes. Virginia was the first state to pass a law on biosimilars, with North Dakota following. California passed a bill that passed in both chambers but was then vetoed by the governor. Thirteen other states filed bills that did not pass. And, New Jersey carried over its 2014 bills to 2015.⁷

While the provisions of the state statutes differ, they do have several things in common:⁷

• FDA must first approve any substitution product as interchangeable for a biological product.
• The prescriber can prevent substitution by stating “dispense as written” or “brand medically necessary.”
• The prescriber must be notified of any allowable substitution made at a pharmacy.
• The patient must be notified that a substitution has been made (and, in some cases, patient consent is required prior to the substitution).
• The pharmacist and physician must retain records of substituted biologic medications.
• The state must maintain a public list of permissible interchangeable products.

In some states, pharmacists who make a substitution in compliance with the law are provided immunity. Groups that oppose notification requirements cite statistics that show states with patient consent laws for generic drugs typically have a 25 percent lower substitution rate than states that don’t.⁸

The Naming Debate

There also is considerable debate concerning the naming of biosimilars, because a name can make or break a biosimilar’s ability to be interchangeable with its innovator biologic. Once again, the BPCI Act did not specifically address how biosimilars would be named. And, groups on both sides of the argument are petitioning FDA to side with them as millions of healthcare dollars are at stake.

Currently, small molecule drugs and their generics carry the same United States Adopted Names (USAN) or International Nonproprietary Name (INN). However, it is still undetermined whether biosimilars will carry the same USAN/INN as their branded counterparts.⁹

On one side of the issue are those who are lobbying for the names to be the same. They say a unique name would be confusing to physicians, pharmacists and patients and could inhibit the prescribing of a biosimilar. In a letter to FDA in July, generic drug makers, Express Scripts and 30 other organizations argued that the INN, administered by the World Health Organization (WHO), has been used with biosimilars in Europe since 2006, as well as other parts of the world, and thus far, there have been no issues of traceability or pharmacovigilance. Not using the INN, they say, would make U.S. biosimilar product names different from those in the rest of the world.

On the other side of the issue are those who argue that a unique name should be given to biosimilars because they are, in fact, not identical. In August, specialty physicians urged FDA to not use the same names, citing the difficulty in copying biologics and, therefore, the difficulty in accurate traceability of adverse events. They argue that even though the products may be safe and effective, they also may differ. Those differences, however small, can have a significant impact on the patient’s response. “It is absolutely necessary for names to be distinct and non-proprietary. You can’t track adverse events without a distinct name,” says Lamotte.

It will be up to FDA to determine if the INN will be used for biosimilars in the U.S. In 2006, FDA sent a position paper to WHO in favor of INN, but with distinct suffixes, which is similar to how Japan handles naming. But, critics of the addition of suffixes to names say those suffixes could be a challenge for pharmacies because they could be dropped from an electronic drop-down menu or may not fit into the electronic prescription database fields.¹

Another issue is the rate at which biosimilars are substituted by pharmacists, which will likely be determined by the naming convention. For example, the American Medical Association recommends that prescriptions of current generic drugs contain the USAN-assigned name for the drug. If this recommendation were followed, a biosimilar with a different USAN designation would not be listed on the prescription, making it less likely to be substituted.⁸

The Purple Book

Recently, FDA published its first edition of the Purple Book (similar to FDA’s Orange Book for the pharmaceutical industry), which lists all approved biologics. As biosimilars are approved, they will be added to the Purple Book so healthcare professionals are able to view them. The Purple Book will use a four-part standard to define biosimilar interchangeability:

• Highly similar with a fingerprint-like similarity
• Highly similar
• Similar
• Not similar

The Regulatory Affairs Professional Society notes that the term “biosimilar” will likely be the catch-all term for noninterchangeable biosimilar products, and the four-part standard appears to indicate that not all approved biosimilar products will be considered interchangeable.¹⁰

The Way Ahead

Since there are no final guidelines at this time, it is likely that approvals will occur on a case-by-case basis. The first biosimilar, Zarxio (filgrastim-sndz), was approved in early March. Zarxio, which is biosimilar to Amgen Inc’s Neupogen (filgrastim) that was originally licensed in 1991 for treating cancer, is approved for the same indications as Neupogen.¹¹

IDF is petitioning for FDA to prohibit immune globulin therapies from being considered as interchangeable until there is a greater understanding of how they will affect patients. According to IDF, “FDA must recognize that there are tremendous variations in the complexity of biologics and the substantial differences in therapeutic responses to biologics from patient to patient. IDF also urges that at which time biosimilars are approved, they are identified with unique names.”¹²

Concerned with making sure a strong voice advocates for immunodeficient patients, the Patients for Biologics Safety & Access (PBSA) coalition was launched in October. A consortium of 22 patient advocacy organizations, including IDF, the Jeffrey Modell Foundation, the American Autoimmune Related Diseases Association and the Platelet Disorder Support Association, is lobbying for adequate patient safety pathways as FDA considers biosimilars and interchangeable biologics.¹³ “Patients need continued access to safe biologic medicines,” says Marcia Boyle, president and founder of IDF, “and as the FDA creates a regulatory pathway to market for biosimilars, we want to make sure the voices and interests of patients are front and center.”

To date, FDA’s CDER has received more than 60 requests from companies wishing to discuss biosimilar development for more than 13 different reference products, not to mention Investigational New Drug (IND) applications for biosimilar development programs.¹ The efforts and concerns for determining a safe and effective regulatory pathway for these products have never been greater. “Right now, we are in a black hole,” says Lamotte. “If there are biosimilars that are proved safe and effective, then we are all for that. But we just need some rules for the road and something that provides confidence and trust that these biosimilars will be safe and effective.”

“Substitutability helped spur the growth of the generic drug industry at an earlier time and is similarly essential to help foster competition in the biologic drug market,” adds Baumgartner. “Ultimately, such competition will spur innovation, improve consumer choice and drive down medical costs. The high standards for approval of biosimilar and interchangeable products mean that patients and healthcare professionals can be assured that, when these products go to market, they will meet the standards of safety, efficacy and high quality that everyone expects and counts on.”