What to know about biosimilars?

The Biologics Price Competition and Innovation Act of (BPCI Act) of 2009 granted responsibility to the FDA for review and approval of a new class of pharmaceuticals referred to as "Biosimilars."⁽¹⁾

The first biosimilar was approved and introduced by the FDA in March of 2015 to combat high prices associated with its competitive “Branded Reference Biologic”, and since then, 56 additional agents have been approved. Their release has prompted questions, comparisons, and confusion regarding as to their place in day-to-day clinical practice. The following article will address these questions as well as the barriers in their way for general usage.

What is a biosimilar?

Unlike traditional medications, which are derived from chemicals the class of drugs referred to as Biologic Branded Reference medications and are derived from living sources such as plant or animal cells, bacteria, yeast, and various viruses.⁽²⁾ Scientists are then able to utilize the living sources to engineer therapeutic proteins, which can be used to treat disease.

In an attempt to provide more affordable medications to patients without introducing added risks the class of drugs referred to as Biosimilars were introduced. Biosimilars are approved through the FDA review process after proving to be as safe and effective as their respective Branded Reference product. Biosimilar refers to the fact that Biosimilars are not exact replicas to their Reference Biologic product, due to that fact that they are derived from living things and cannot be made as exact copies of the branded biologic, resulting in a lack of exactness.⁽³⁾ Currently there are 57 FDA-approved Biosimilar products sharing the marketplace with 17 previously approved biologic reference products. ⁽⁴⁾

A key provision of the BPCIA was to allow the newly defined biosimilar products to piggy-back on safety and efficacy data for previously FDA-approved biologic reference products.⁽⁵⁾ The FDA evaluates each proposed biosimilar product individually, and works with the manufacturer to determine the scope and extent of testing necessary to demonstrate biosimilarity to the previously approved referenced biologic product.(6) The approved pathways intention is to expedite the approval process for biosimilar products without requiring expensive and lengthy clinical trials. This amended pathway helps reduce the time and cost in the development of biosimilars without compromising either safety or effectiveness. ⁽⁶⁾

What differences exist between biosimilar and generic drugs?

There has been a substantial amount of confusion since the release of the initial biosimilar drugs based on previous misperceptions regarding the development and approval of generic drugs. Much of the confusion stems from the fact that each type of drug is developed with the intention of substituting it for a previously approved Branded and Approved FDA drug.

Generic drugs are made from chemicals and are therefore able to be exact copies of the chemical makeup of the previously approved branded drug. Generic drugs work in the same manner as the branded drug, and can substitute for the branded drug while being used to treat the same disease(s) as the branded drug.⁽³⁾ As described previously, Biosimilar drugs are not exact copies of previously approved Biologic drugs due to the fact that they are derived from living substances and therefore cannot be exact replicas. Several of the top Branded Biologic Drugs along with their associated Biosimilar drugs include:

Humira (Adalimumab); Remicade (Infliximab); Rituxan (Rituximab); Enbrel (Etanercept); Herceptin (Trastuzumab); and Avastin (Bevacizumab)

Additionally, biosimilar drugs initially were required to undergo a special approval after FDA approval order to be considered “interchangeable” with the associated branded reference product. The area of “interchangeability” has appreciated a growing amount of attention due to various legal proceedings addressed within the approval process and will be discussed in further detail later in the paper. ⁽³⁾

Much of the confusion centers around the fact that generic drugs and biosimilar drugs have many commonalities as listed below:⁽³⁾

They are both tested and compared to a brand name drug in studies.
The drugs tested against have already been approved by the FDA.
They both go through a shortened FDA review process compared to the previously approved branded products.
When approved, they are both deemed to be as safe and effective as the brand name drugs.
Both drugs are likely to be less expensive than their brand name drugs

Are biosimilars safe?

Biosimilars have become treatment options that are FDA-approved based on robust analytical and clinical comparisons with their reference biologic branded product. ⁽⁷⁾ At the time of their initial approval, the full safety profile of a biosimilar is accepted based on data reviewed from the previously approved reference biologic.

In one of the largest reviews conducted on eight approved and marketed biosimilar drugs over a period of 18 years, which represented more than 1.3 billion patient days of treatment concluded that the overall benefit-risk profile for the eight biosimilars was favorable and consistent with their respective reference biologic drugs.(7) Additionally, the authors concluded that it is reasonable to believe that similar conclusions regarding safety can be reached for other biosimilars based on the high standards in place by the major health authorities which includes the FDA.⁽⁷⁾

The World Health Organization (WHO) recently published their findings, which included literature searches conducted on the long-term efficacy, safety, and immunogenicity, to evaluate post-marketing experience with biosimilars. The report estimated that the cumulative exposure to European Union (EU)-approved biosimilars included more than 2 billion patient treatment days in 2020.⁽⁸⁾ In the EU, no biosimilar products have been withdrawn from the market for safety reasons and no biosimilar-specific adverse effects have been added to the product information.⁽⁸⁾

The data are clear, and the evidence demonstrates that biosimilar drugs are safe and effective in the treatment of select diseases as compared to their reference biologic product.

What barriers exist to biosimilar usage?

Since the release of the initial biosimilar drugs in 2015, and the hopes for patients to gain access to less expensive, safe, and effective alternatives, there has been a constant concern focusing on the barriers that have limited their usage. Initial projections predicted that the introduction of biosimilars had the potential to reduce biologic spending by $54 billion between the years 2017 and 2026. ⁽⁹⁾

As each newly approved biosimilar products gains FDA approval there exists an increase in competition, which besides expanding the availability of proven safe and effective products, but at a lower cost, anticipated to be about 30% lower than the original reference biologics. ⁽¹⁰⁾

Despite the potential benefits with the release of biosimilars, no less than four reasons have been identified which have reduced their broader acceptance: ⁽¹⁰⁾

Provider awareness and acceptance- The need for resources to educate key health care providers and formulary decision makers.
Patient awareness and acceptance- The need for resources to educate patients regarding the newly available therapies along with associated benefits such as costs without compromise in effectiveness and safety.
Treatment selection- Included within the education of healthcare providers and formulary decision makers is the need to provide those approved indications for the approved biosimilar along with the key components of “Drug Interchangeability” where relevant, as discussed below.
Policy variation and authorization struggles- The use of any specific biosimilar will vary widely and can be dependent on commercial payers and their respective formulary plans. With the growing number of biosimilars approved for a previously approved Biologic Reference product, commercial payers and formulary managers can select from a growing list of biosimilar products, based on price, availability, and convenience. Currently, the branded Biologic product Humira has no less than 10 available Biosimilar (adalimumab) products for commercial payers and formulary managers to choose from.

What controversies exist with biosimilar drugs and interchangeability?

An interchangeable biosimilar drug is an FDA-approved drug, which depending on state pharmacy laws can be dispensed to a patient for the Referenced Biologic Product without any type of interaction with the prescribing healthcare provider. ⁽¹¹⁾ Not all biosimilars are interchangeable, and as of this writing only 13 biosimilar drugs have undergone the extra evaluations required in order to be granted interchangeable status.⁽¹²⁾ During the initial approvals of biosimilars, a lack of experience with the new class of drugs prompted regulatory agencies to add testing as a way to assure safety and effectiveness before widening the utilizations net. This is what created the special designation “Interchangeability.”⁽¹³⁾

However, due to the valuable experience appreciated during the last 10 years with biosimilar drugs, the FDA has concluded that biosimilars possess the same high standards as their associated reference products and have decided that additional studies will not routinely be necessary to determine Interchangeability.⁽¹²⁾This should be a major benefit to the consumer by increasing the number of available safe and effective drugs in treating disease at a price tag, which will be lower than that associated with the branded reference product like what we had experienced previously with generic drugs.

Conclusion

During the last 10 years, much has been learned and appreciated regarding the availability and value associated with biosimilar drugs. As previously experienced during the early introduction of generic drugs to the marketplace, biosimilars have shared the common skepticism that comes with change. However, over time, and with growing experience we begin to experience a breakdown in those barriers, which made early adoption challenging. We believe the future is bright for biosimilars as the experiences being appreciated continue to help facilitate their growing introduction into the healthcare marketplace.

The result should be a good outcome for the consumer as we should expect to see a growing number of available products proven to be safe and effective while able to reduce prescription costs without compromise. One word of caution based on what we had seen previously with the generic marketplace. If continued priorities center around achieving the lowest possible price (Race to the Bottom) we could again experience marketplace disruptions with manufacturers leaving the marketplace as witnessed within the generic marketplace. ⁽¹⁴⁾

Research by Alan H. Mutnick, Director of Pharmacy Strategic Sourcing Memorial Healthcare System (Retired) and Lan Mai Trinh, Research Associate.

References:

What to know about biosimilars?

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