On Wednesday, January 7th, the FDA Oncologic Drugs Advisory Committee unanimously recommended approval of Sandoz’s EP2006, a biosimilar for filgrastim (Neupogen). EP2006 is a recombinant granulocyte colony-stimulating factor used to boost white blood cells after cancer treatments that deplete these necessary infection-fighting cells. If FDA-approved, this would be the first true biosimilar in the U.S. and would have a brand name of Zarxio. The FDA noted in their briefs that EP2006 was “highly similar” to the brand biologic and had “no clinically meaningful differences between the proposed product and the reference product in terms of safety, purity, and potency”. The FDA stated that “robust” pharmacokinetic and pharmacodynamic comparative studies supported biosimilarity with the original filgrastim. Legal action over patent protection may still interfere with a launch any time soon.

I’ll admit, as a pharmacist the topic of biosimilars peaks my interest. Europe has been marketing biosimilars for 10 years now, and the Food and Drug Administration (FDA) is currently developing long-awaited standards so that this process can occur in the U.S. But I have many questions:

• What is the current biosimilar status is in the U.S. and when will we see the first biosimilar?
• What biologics are in line to be the first biosimilars?
• Where will I find information about biologic interchange with biosimilars?
• Can a pharmacist automatically substitute a biosimilar for a biologic?
• Will a biosimilar still be as expensive as many of the biologics?
• What lessons can we learn from the European Union biosimilar program?

The first true biosimilar may be approved in the U.S. soon. Here’s a few facts about biosimilars to get you up to speed.

Why Biosimilars?

The general process to approve generics for traditional (small-molecule) drugs, like Lipitor(atorvastatin) and Celebrex (celecoxib) is well-known. Consumers have enjoyed these savings for years, especially since 2012 when many top medications became available generically during the “patent cliff”.

In a nutshell, generic drug makers submit an abbreviated new drug application (aNDA) to the FDA in anticipation of, or after, a brand medication patent expiration. Based on the proven bioequivalence of the active ingredient(s), plus inclusion of the same use, dosage form, strength, route of administration, and labeling, generic manufacturers can bypass much of the expensive and time-consuming clinical studies done by the original manufacturer, according to the FDA. In other words — no need to reinvent the wheel. But the process for biologics and biosimilars is somewhat different.

Biosimilars are just that; similar because they do not have to be exact copies of the active ingredient, as with small-molecule drugs. The Biologics Price Competition and Innovation Act of 2009 (the BPCI Act) allowed the creation of an abbreviated licensure pathway for biological products that are shown to be interchangeable with an already FDA-approved biological product. Under the new law, a biological product may be demonstrated to be “biosimilar” if data show that the product is “highly similar” to an already-approved biological product. The BPCI Act aligns with the FDA’s longstanding policy of permitting appropriate reliance on drug science that has already been established, thereby saving time, resources and unnecessary duplication of animal testing or human clinical trials. Some clinicians and patients are concerned if a biosimilar is not exactly the same as its counterpart, how can they rely on its safety and effectiveness?

First things first: What exactly is a biological product?

According to the FDA, biological products can include a wide range of products including vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, and proteins. Unlike most traditional, small-molecule drugs that are manufactured through chemical processes, biological products are usually made from human and/or animal materials inside their cells. Biological products — for example, Enbrel (etanercept) or Humira (adalimumab) are referred to as “large-molecule” drugs because they are larger in structure and have a more complex structure than small-molecule drugs, Such products may also be derived from natural sources or produced synthetically.

What is a biosimilar?

A biosimilar is a biological product that is “highly similar” to a U.S.-licensed reference biological and for which there are no clinically meaningful differences between the biological product and the original branded product in terms of safety, purity, and potency of the product. However, a biosimilar is not considered a “generic” in the same way that a traditional drug is determined to be a generic. As with generics, cost savings for healthcare systems and the consumer are expected with biosimilars and will be significant. According to the RAND Corporation, biosimilars could save the U.S. health system close to $44 billion in the next ten years.

Biologics are complicated, and so is their manufacturing process.

It is much easier to create and analyze a generic for a traditional drug product because it consists of a pure chemical substance, but manufacturing large molecule biologics is a more complex task. Manufacturing changes will certainly lead to slight differences between biologics and biosimilars. Proteins can be altered when manufacturing processes change, and there is concern that this may alter how the biosimilar product performs clinically in the patient. Much debate centers around this issue.

FDA is addressing this problem. As noted by the agency “changes in the manufacturing process, equipment or facilities may require additional clinical studies to demonstrate the product’s continued safety, identity, purity and potency.” Makers of biosimilar drugs will also be responsible for proving to the FDA that their products have similar outcomes, and that switching back and forth between the brand and the biosimilar will be safe and effective for the patient. If these studies are not done, the product cannot be called a “biosimilar.” These types of transition studies are not typically conducted with small-molecule, non-biologic agents.

But wait, haven’t biosimilars been available in Europe for years?

Yes, several biologics have already lost patent protection in Europe. An established legal pathway for biosimilars has been in the European Union since 2005. Several biosimilars, including somatropins, filgrastims, and epoetins, have been licensed and marketed in the European Union (EU). Biologics that have already expired in Europe include Neulasta(pegfilgrastim), Remicade (infliximab), Mabthera (rituximab, known as Rituxan in the U.S.), andLovenox (enoxaparin).

Other top biologics facing future patent expiration include Humira (2018), Enbrel (2015), andAvastin (2019), all well-known brands in the U.S. According to IMS, the biologics market accounts for 27% of the pharmaceutical sales in Europe and is growing at 5.5% vs. total market growth of 1.9% between 2012 and 2013.

France was the first EU member-state to initiate automatic pharmacist substitution for biosimilars in February 2014.

Common concerns with biosimilars.

However, as learned from the European experience, there are concerns about product-related and clinical issues with biosimilars.

• Immunogenicity can occur with biologics and biosimilars alike. Structural alterations in the biosimilar compound can lead to “immunogenicity”, inactivating the therapeutic effects of the treatment, and possibly causing side effects. Newly introduced substances during the manufacturing process with biosimilars may lead to immunogenicity not seen with its corresponding biosimilar.
• Some clinicians express uncertainty about using biosimilars because they are not identical to the innovator product. However, even innovator biologics can have differences within the same batch, so this is not a new concept in biotechnology. Small differences can usually be picked up early on in manufacturing with sensitive testing, and may not be clinically significant.
• Post-marketing, Phase IV safety studies should be initiated to actively monitor for previously unreported side effects.
• Determination of valid endpoints measuring biosimilar activity in studies.
• Use of biosimilars for unapproved or “off-label” indications based on extrapolated data may raise safety issues.
• Concerns about automatic substitution at the pharmacy level due to differences in injection device, preparation, and handling of the biosimilar, which may increase the risk of a medication error or affect adherence to treatment.
• Concerns over naming standards; biosimilars with the same exact name as the corresponding biologic may be assumed to be identical and automatically substitutable by health care provider or patient.

Are There FDA Biosimilar Standards?

Biological products are complex products and the pathway to approval is an even more complicated task. Since passage of the Affordable Care Act in 2010, the FDA has been establishing standards for licensure to ensure the safety and effectiveness of biosimilars. A working group consisting of members from both the Centers for Drug Research and Evaluation (CDER) and the Center for Biologics Evaluation and Research (CBER) are tasked with addressing product-specific review and issues relating to scientific methodology.

According to FDA, “scientists, clinicians, and other personnel at FDA are currently working out the details of the review and licensure process.” When the first biosimilar will be on the U.S. market is not known. It appears biologic brand products will have exclusivity for 12 years from the date of first licensure before a biosimilar can be approved.

In the U.S. roughly ten biosimilar products may be available for FDA review in the next decade due to patent loss. Examples include Neulasta (pegfilgrastim), Herceptin (trastuzumab), Rituxan(rituximab), Remicade (infliximab), and Aranesp (darbepoetin alfa). While the biologics Neupogen(filgrastim) and Granix (tbo-filgrastim) are both filgrastim products, they each went through the full BCPI Act approval process and therefore are not considered “biosimilar”. Companies such as Teva, Hospira and Sandoz are now developing biosimilar products; however, some manufacturers are awaiting the final FDA biosimilar standards for clarification.

In the U.S., will a pharmacist be able to automatically substitute a biosimilar for a biologic without contacting the prescriber?

According to the FDA, this can only happen if the products are deemed “interchangeable.” In general, biosimilar biological products cannot be dispensed in place of another biological product unless a physician or other healthcare professional prescribes the biosimilar product. However, if the product has been determined to be interchangeable, which means it is biosimilar to the reference product, and will produce the same clinical result as the reference product in any given patient, then they are substitutable. Interchangeable also means the original biologic and the new biosimilar can be switched back and forth in patients without a risk of diminished safety or efficacy. Pharmacists will be responsible for knowing which biological products are interchangeable.

The Purple Book

Once biosimilars are marketed, The Purple Book will be to go-to resource for pharmacists and other health care providers interested in making an interchange between a reference biologic and a biosimilar. Similar to The Orange Book used to compare generic products to their brand name counterparts, The Purple Book has been developed by the FDA to list each reference biological product and the corresponding biosimilar and interchangeable biological products. Those biosimilars designated as interchangeable will have no clinically important differences from the original product. However, variation in formulation, delivery device, indications, and routes of administration may be acceptable.

The Purple Book also lists information relating to exclusivity and patent protection of the reference biological product. The Purple Book will serve as a helpful resource to be able to determine the earliest date at which a biosimilar or interchangeable product could be licensed. The official title of the Purple Book is “Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations”; the Purple Book is much easier, don’t you think?

The Question of Cost

The size of the molecule is not the only thing large about biologics. As reported in The Economist, biologics could encompass over 30 percent of total big pharma sales by 2023. Even though biologics are hard to make, they can be financially rewarding for a manufacturer when the product is a success. In fact, seven of the top 10 drugs by sales in the U.S. in 2014 were biologics, and understandably so.

Consider this — the average per patient revenue for Avastin (bevacizumab), a cancer treatment, was over $66,000 in 2014. AbbVie’s Humira for rheumatoid arthritis and other autoimmune conditions was the top selling biologic in 2014 with over $6 billion in revenue. Similar dollar figures pop-up for other biologics — Lantus, Enbrel, Remicade, Rituxan, Neulasta, and Avastin — all found in the top 10 drugs by sales for 2014, according to EvaluatePharma. Revenues in 2014 for these drugs ranged from $3 billion to $5.7 billion in sales. Couple that with the delay in biosimilar standards, and even biologics with a valid patent expiry still enjoy significant market share. Epogen (epoetin alfa) was first launched in 1989, with 2012-2013 patent expirations in the U.S., but it still sees no biosimilar competition.

How payors will handle the burgeoning cost of biologics and biosimilars is another question that is not yet fully answered. Insurance groups are pushing back on the price tags, and for patients who lack adequate insurance, potentially life-saving biologic therapy can be completely out of reach.

Future discounts on biosimilars are uncharted territory, as well. As reported by SeekingAlfa, Hospira has noted biosimilars in the U.S. will most likely will be sold “at discounts of 20 to 40 percent from the branded competitors, but some consultants put the discount closer to 10 to 20 percent.” A 10 to 40 percent discount for Avastin could reap $6,000 to over $24,000 annual savings per patient. That is significant in the healthcare system, but even with the largest discount, an Avastin biosimilar still might approach an annual sticker price of $42,000 per patient, hardly a bargain for the individual person.

Sources:

Leigh Anderson is a Senior Editorial Pharmacist at Drugs.com