What Are Biosimilars? Top Facts You May Not Know
What Is A Biosimilar?
A biosimilar is a biological product that is very similar to a reference biologic and for which there are no clinically meaningful differences in terms of safety, purity, and potency. An example of an approved biosimilar is Amjevita (adalimumab-atto), the first biosimilar approved for the blockbuster Humira (adalimumab) used to treat rheumatoid arthritis and psoriasis, among many other uses.
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, biosimilar cost savings for healthcare systems and the consumer are expected to be significant. According to the RAND Corporation, biosimilars could save the U.S. health system close to $44 billion in the next ten years.
What is a Biologic?
If a biosimilar is a biologic, then what is a biologic? Biological products can include a wide range of products including vaccines, blood components, gene therapy, tissues, and proteins, like monoclonal antibodies and cell signaling proteins. Unlike most chemically-derived small-molecule drugs, biological products are generally derived from a living organism, such as humans, animals, microorganisms or yeast. Biologics are used to treat patients with cancer, kidney diseases and autoimmune diseases, such as rheumatoid arthritis and Crohn's disease.
For example, Enbrel (etanercept) or Humira (adalimumab) are referred to as “large-molecule” drugs because they are larger and more complex in structure than small-molecule drugs. These products are very expensive, often in the tens-of-thousands of dollars per year, due to costs linked to complicated development and manufacturing. Often, patients will need to access these medications through a specialty pharmacy.
Are Biosimilars Exactly The Same As The Biologic?
Biosimilars are just that; similar because they do not have to be exact copies of the active ingredient, as with small-molecule drug generics. In 2010, the President signed into law an abbreviated approval pathway for biologics to encourage production, create competition, increase treatment options and reduce healthcare costs. 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 new law, known as the Biologics Price Competition and Innovation Act of 2009 (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. How the BPCI Act will fare through an ACA repeal under the Trump administration has yet to be seen.
Zarxio: A Biosimilar to Neupogen
In March, 2015 the FDA approved the first U.S. biosimilar -- Sandoz’s Zarxio (filgrastim-sndz), the biosimilar for filgrastim (Amgen's Neupogen). Zarxio is a recombinant granulocyte colony-stimulating factor used to boost white blood cells after cancer treatments that deplete these necessary infection-fighting cells. Zarxio is highly similar to the brand biologic and has no clinically meaningful differences with Neupogen in terms of safety, purity, and potency. The FDA stated that “robust” pharmacokinetic and pharmacodynamic comparative studies supported biosimilarity with the original filgrastim.
Inflectra: A Biosimilar to Remicade
After Zarxio, Inflectra (infliximab-dyyb) by Celltrion was the second biosimilar approved in the U.S. Inflectra, a tumor necrosis factor (TNF) blocker, is biosimilar to Janssen’s Remicade (infliximab) originally approved in 1998.
Inflectra can be prescribed for the same indications as Remicade, including rheumatoid arthritis, Crohn’s disease, ankylosing spondylitis (spine arthritis), ulcerative colitis, psoriatic arthritis, and plaque psoriasis.
Erelzi: A Biosimilar to Enbrel
In August 2016 the third biosimilar, Sandoz's Erelzi (etanercept-szzs), was FDA-approved. Erelzi is biosimilar to Amgen’s tumor necrosis factor (TNF) blocker Enbrel. Erelzi is the first approved biosimilar for etanercept, and is used for the same five indications for Enbrel: rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis.
It’s important to note that Erelzi has been approved as a biosimilar, not as an interchangeable product. Physicians must write the prescription specifically for Erelzi, as pharmacists cannot automatically substitute Erelzi for Enbrel.
Amjevita: A Biosimilar for Humira
Amgen’s Amjevita (adalimumab-atto) is the first U.S. biosimilar approved for adalimumab (Humira) in September 2016. It is used for the treatment of seven inflammatory diseases, including rheumatoid arthritis, Crohn's disease, and plaque psoriasis. Amjevita is an anti-TNF-α monoclonal antibody that has the same amino acid sequence as adalimumab.
The pharmacist needs direction from the prescribing doctor to substitute Amjevita for Humira, as it is not approved as an interchangeable product. Common side effects include increased risk of infections and injection site reactions. Amjevita is available in a pre-filled syringe or auto-injector.
Renflexis: A Second Remicade Biosimilar
In April 2017, the FDA approved Renflexis (infliximab-abda), a tumor necrosis factor (TNF) blocker from Samsung Bioepis that is biosimilar to Remicade (infliximab).
Renflexis is used for the treatment of Crohn’s disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis. The biosimilar must be shown to have no clinically meaningful differences in terms of safety and effectiveness from the reference product Remicade. Only minor differences in clinically inactive components are allowable in biosimilar products. The first biosimilar to Remicade, Pfizer’s Inflectra (infliximab-dyyb) was approved by the FDA in April, 2016.
How Are Biosimilars Named?
In January 2017 the FDA issued a guidance on naming conventions for biosimilars. According to the guidance the nonproprietary name designated "will be a proper name that is a combination of the core name and a distinguishing suffix that is devoid of meaning and composed of four lowercase letters. FDA is continuing to consider the appropriate suffix format for interchangeable products.
In the current naming convention, FDA has designated guidelines for approved biosimilar nonproprietary names that incorporates four lowercase letters (a suffix). FDA has stated drug companies can propose up to 10 suffixes for each new biosimilar.
Currently, the newly licensed biosimilars (none of which are deemed interchangeable by the FDA) have gained the unique 4-letter suffix. Some are linked with the manufacturer (filgrastim-'sndz' for Sandoz), and some apparently random (infliximab-dyyb), but going forward it appears they will not be linked with the manufacturer.
Can Pharmacists Automatically Substitute a Biosimilar for a Brand?
It depends. In general, biosimilars cannot be dispensed in place of another biological product unless a physician or other healthcare professional specifically prescribes the biosimilar product by name.
However, according to the FDA, automatic substitution can happen if the products are deemed interchangeable. If the product has been determined to be interchangeable, then it is biosimilar to the reference product AND will produce the same clinical result as the reference product in any given patient. 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, and can check The Purple Book to find these products.
The Purple Book
The Purple Book will be the 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 product.
Those biosimilars designated as interchangeable will have no clinically important differences from the original product. Variation in formulation, delivery device, indications, and routes of administration may be acceptable.
The Cost of Biosimilars
The size of the molecule is not the only thing large about biologics. Seven of the top 10 drugs by sales in the U.S. in 2014 were biologics. In fact, AbbVie’s Humira sales in 2015 tipped at just over $14 billion, the number one seller. And as reported in The Economist, biologics could encompass over 30 percent of total big pharma sales by 2023.
How payers - and patients - will handle the burgeoning cost of biologics and biosimilars is a question that must be 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.
As reported by SeekingAlfa, Hospira has noted biosimilars in the U.S. will most likely will be sold at discounts of 10 to 40 percent from the branded competitors.
Are There Concerns With Biosimilars?
Biosimilars have been available in Europe for years, and there have been some product-related and clinical issues raised with biosimilars. For example:
- Will use of biosimilars for unapproved or “off-label” indications based on extrapolated data raise safety issues?
- Should post-marketing, phase IV safety studies be initiated to actively monitor for previously unreported side effects?
- Will clinicians be concerned that biosimilars are not identical to the innovator product, limiting prescribing?
- Could new types of immunogenicity be seen with biosimilars due to newly introduced substances during the manufacturing process?
- Will naming conventions lead to biases in prescribing or not?
Which Biosimilars May Be Up for Approval Next?
In the U.S., at least six more biosimilar products may be available for FDA review in the next decade due to patent loss. Examples include:
- Avastin (bevacizumab)
- Neulasta (pegfilgrastim)
- Herceptin (trastuzumab)
- Rituxan (rituximab)
- 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 rapidly working in this area and developing biosimilar products.
The Case of Granix (tbo-filgrastim)
There's always an exception, and this is no different with biosimilars. Teva's Granix (tbo-filgrastim) is not technically considered a biosimilar to Neupogen (filgrastim) because it was filed with a full BLA and clinical trials to determine effectiveness before the the publication of FDA’s new biosimilar pathway. FDA approved Granix to treat neutropenia, low white blood cells caused by receiving cancer treatment with chemotherapy. Even though Granix and Neupogen slightly in structure, their effectiveness and safety are not significant. Tbo-filgrastim's effectiveness was evaluated in a clinical study of 348 adult patients with advanced breast cancer receiving treatment with the anti-cancer drugs doxorubicin and docetaxel.
Granix's "tbo" suffix is used to distinguish it's nonproprietary name from the reference biological product Neupogen (filgrastim).
Finished: What Are Biosimilars? Top Facts You May Not Know
- The Economist. January 3rd, 2015. Business. Pharmaceuticals. Going large. p.47-48. Accessed October 30, 2016 at http://www.economist.com/news/business/21637387-wave-new-medicines-known-biologics-will-be-good-drugmakers-may-not-be-so-good
- U.S. Food and Drug Administration (FDA). Drugs. Information for Consumers. Biosimilars. Accessed October 30, 2016 at http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm241718.htm
- U.S. Food and Drug Administration (FDA). Background Information: Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations. Accessed May 18, 2017 at http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm411424.htm
- IMS Institute for Healthcare Informatics. Assessing biosimilar uptake and competition in European markets. October 2014. Accessed January 4th, 2014.
- FiercePharma. The Top 10 patent losses of 2015. Stanton T. Accessed May 18, 2017 at http://www.fiercepharma.com/special-reports/top-10-patent-expirations-2015
- U.S. Food and Drug Administration (FDA). Drugs. Implementation of the Biologics Price Competition and Innovation Act of 2009. Accessed May 18, 2017 at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ucm215089.htm
- Seeking Alfa. Amgen and Its Biosimilar Competition. Accessed May 18, 2017 at http://seekingalpha.com/article/846451-amgen-and-its-biosimilar-competitors
- EvaulatePharma. Budget Busters: The shift to high-priced innovator drugs in the USA. Accessed May 18, 2017 at http://info.evaluategroup.com/rs/evaluatepharmaltd/images/SV2014.pdf.
- Weise M. Bielsky M. De Smet K. et al. Biosimilars: What clinicians should know. Blood. 2012;120:5111-17. Accessed May 18, 2017 at http://www.bloodjournal.org/content/bloodjournal/120/26/5111.full.pdf?sso-checked=true
- Biosimilars pose problems for Medicare beneficiaries. Formulary Journal. Accessed May 18, 2017 at http://formularyjournal.modernmedicine.com/formulary-journal/news/biosimilars-pose-problems-medicare-beneficiaries?cfcache=true
- Nonproprietary Naming of Biological Products. Guidance for Industry. U.S. Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Center for Biologics Evaluation and Research (CBER). January 2017. Accessed May 18, 2017 at https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm459987.pdf