Biologics: What Are They and Why Are They Different?
When I think back to pharmacy school, one of the first courses I took was organic chemistry, in which we learned about the structure, properties, and composition of molecules and how various reactions created new, more extensive compounds. Even though this sounds complex, this does not even compare to the complexity of a biological agent.
 
Although there are several different types of biological products, which the FDA notes includes proteins, monoclonal antibodies, and vaccines with little in common. For example, biologic drugs are large molecules typically manufactured from living cells and, therefore, are extremely difficult to produce or reproduce. In fact, there can be variations of acceptable range within the same manufacturing process because biologics are processed using living cell-based technology and the make of these agents is not easily identifiable.
 
For this reason, they are also highly sensitive to storage and handling processes and typically have a shorter shelf life than your average oral medications. So, why research, develop, and ultimately manufacturer such complex, sometimes costly medications you might ask? Because they are able to effectively treat a variety of medical conditions that previously had limited to no other treatments available, thereby changing the lives of patients with conditions such as rheumatoid arthritis, cancer, and anemia, just to name a few.
 
Generic Biologics
Although biosimilars and generic medications are both versions of brand name drugs, because of the complexity of biologics, existing regulations in place, such as the Hatch-Waxman Act (which encourages manufacturers to market generic drugs to create competition and lower health care costs) do not apply to biologics. However, approximately 8 years ago, the Biological Price Competition and Innovation (BPCI) Act was passed to expedite the approval of biological products that have shown biosimilarlity or interchangeability with a biologic drug already approved by the FDA. Biosimilarity refers to a biologic that has demonstrated similar efficacy and safety with no clinically-meaningful differences from the FDA-approved reference product.
 
The FDA allows biosimilarity to be proven through an analysis of the reference product’s purity, chemical identity, and bioactivity. Interchangeability, however, refers to a biologic being that can be substituted for the reference product by a pharmacist requiring the approval of the health care provider who prescribed the reference drug. To attain interchangeability, additional information must be provided that ultimately demonstrates the biosimilar product produces the same clinical result as the reference product without compromising safety or efficacy by alternating or switching between the products. To date, no biosimilars have received FDA approval for interchangeability.
Since the passage of the BPCI Act, approximately 12 biosimilars have been approved by the FDA, yet only 3 are currently available at the time of this writing. These biomsiliars include Zarxio, indicated for the treatment of low neutrophils, and Inflectra and Renflexis, both indicated for the treatment of rheumatoid arthritis.
 
Limited Utilization to Date
Despite being available in the market, use of these products to date have not taken off. There are a number of reasons why we have not seen high utilization of biosimilars in the United States like we have seen in other areas of the world, such as the European Union. Some of these factors include the lack of regulatory direction regarding interchangeability, which leads to the inability to automatically substitute a lower cost alternative when dispensing a medication, as well as legal actions between manufacturers regarding patent litigations.
 
Additionally, similar to what was observed initially with generic medications, there is a lack of awareness and confidence from both patients and prescribers regarding biosimilars. Finally, the cost difference between the branded and biosimilar product may not be enough to incentivize a change in prescribing patterns and patient demand. Some of these reasons are discussed in more detail below.
 
Regulations
One of the reasons biosimilar use has seen slow adoption in the United States is because of the lack of clarity and guidance on the approval process for both biosimilarity and interchangeability. During the life of the BPCI Act, the FDA issued draft guidance on the parameters that will determine biosimilarity, such as structural and functional studies, as well as additional animal and clinical studies that may be needed if requested.
 
This will be determined on a case-by-case basis, which leaves room for variation and misinterpretation among manufacturers seeking FDA approval for a biosimilar and ultimately extends the timeframe by which these medications can gain approval. Additionally, it was not until 2017 that the government released a draft guidance regarding the parameters necessary for a biosimilar to attain interchangeability status.
 
Some of the necessary information may include, but is not limited to, an “analysis of the mechanism of action in each condition of use including binding, dose and pattern of molecular signaling upon engagement of the target receptor, the pharmacokinetics and distribution of the product in different patient populations, and differences in expected toxicities in each condition of use,” the FDA wrote.
 
A few things of note regarding interchangeability. First, although generics were able to gain approval for an abbreviated new drug application by proving bioequivalence to the brand medication, this is clearly not the case for biologic drugs.
 
Although this is completely understandable based on the complexity of biological products, the cost to perform clinical trials to demonstrate interchangeability with a reference product may diminish the savings we might see with biosimilar products and deter manufacturers from seeking interchangeability versus only biosimilar status. On the other hand, without interchangeability status, pharmacists are unable to automatically substitute a biosimilar for a biological product without physician consent, limiting the use of these products in practice.
 
Patent Litigations  
Also contributing to the limited use and launch of biosimilars into the marketplace are the legal actions filed by brand biological manufacturers against biosimilar manufacturers. Contrary to non-biologic medications that branded manufacturers eventually stopped promoting due to increased competition and cost savings provided by generic medications, manufacturers of biological agents have continued to protect their patents despite the BPCI Act.
 
For example, AbbVie, the manufacturer of Humira, reached a settlement with Amgen, the manufacturer of Amjevita, delaying the launch of the biosimilar until 2023 despite receiving biosimilar approval in 2016. A similar situation occurred with Erelzi, Novartis’ biosimilar for Enbrel, in which Amgen was able to successfully delay launch of the product until 2028. Multiple situations such as these continue to occur as biosimilars seek FDA approval, delaying the timeframe it takes to receive approval and launch the product into the marketplace.
 
Physician and Patient Pushback          
Another potential contributing factor to the low use of biosimilars in general may be because approved biosimilars do not have interchangeability status. This may cause hesitation on physician’s part to switch patients from medications they are familiar with to products that have only been shown to be highly similar to the reference product.
 
Patients using these biological agents are dealing with rare conditions accompanied by immediate consequences if not managed appropriately. Therefore, there may also be hesitancy on the part of the patient to try a biosimilar product, even if it means a less costly option. Further education and additional testing may be needed to push biosimilar acceptance along. However, this may diminish some of the cost savings that could be achieved with biosimilars. 
 
Lowest Net Cost    
Finally, as it relates to cost, biosimilars have not truly been the lowest cost option that many were anticipating when the BPCI Act was first passed. Some of this may have been a misunderstanding since generic drugs typically represented an 80% to 90% discount from branded medications. Although we will likely never see such deep discounts on biosimilars, 30% to 40% was the anticipated discount; however, take Inflectra for example.
 
When it first launched, the wholesale acquisition cost was $946 per vial rather than $1113 for a comparable vial of Remicade, representing only a 15% discount off the reference product. The price of Inflectra was later adjusted when Renflexis, another biosimilar to Remicade, launched at a 35% discount. The initial savings was not all that compelling to payers, especially if you consider another dimension of the health care system—rebates. Rebates on the branded product could bring the cost of Remicade even lower than any biosimilar option.
 
The Future of Biosimilars
The intent of the BPCI Act was to create a pathway for approval for biologic products that have demonstrated biosimilarlity or interchangeability with an FDA-approved drug in order to drive competition and, potentially, health care savings to the industry. However, for various reasons that have been discussed, there has been limited launch and utilization of these products to date.
 
Recognizing some of these limitations, the FDA recently released a Biosimilar Action Plan in an effort to expedite the use of these products. The FDA said the plan is focused on 4 key areas, including:
  1. Improving the efficiency of the development and approval processes for both biosimilarity and interchangeability products.
  2. Maximizing scientific and regulatory clarity for biosimilar manufacturers.
  3. Developing effective communications to improve understanding of biosimilars among patients, clinicians, and payers.
  4. Supporting market competition by reducing gaming of FDA requirements or other attempts to unfairly delay competition.
Conclusion  
As specialty continues to grow and the industry is tasked with finding ways to ensure positive health outcomes and control costs, biosimilars present a cost-saving opportunity for all stakeholders involved in the health care system. Although payers can potentially begin to shift the paradigm of biosimilar utilization by encouraging prescribers and patients to try alternative options through utilization management or formulary coverage, it remains difficult to truly gain traction with biosimilars until all stakeholders involved are aligned including the patient, prescriber, payer and manufacturer.
 
About the Author
Lauren Meyer earned her Doctor of Pharmacy degree from the Duquesne University School of Pharmacy and is currently enrolled in the Master of Science in Pharmacy Business Administration (MSPBA) program at the University of Pittsburgh, a 12-month, executive-style graduate education program designed for working professionals striving to be tomorrow’s leaders in the business of medicines.  She has spent the past several years working as a clinical advisor assisting employers with their pharmacy benefit management strategy. Prior to this experience, she completed a PGY-1 managed care residency.