As the patents and exclusivity periods of blockbuster biologics are set to expire, biosimilar pharmaceuticals continue to emerge as a cost-effective, alternative treatment choice. With 3 new biosimilars approved by the FDA thus far in 2018, the biosimilar landscape in the United States is a hot topic of discussion.
 
There have been 12 FDA-approved biosimilars since 2015, but these approvals are accompanied by a host of legal challenges and opportunities that have limited the use of these drugs and increased competition among biosimilar manufacturers.
 
Pharma, payers, and the FDA are seeking to provide innovative strategies to contain costs while improving access to safe and effective treatments. Future market conditions suggest that specialty pharmaceuticals will drive future pharmacy costs.
 
The pipeline continues to be dominated by biotech, which are typically high ticket items that can receive a longer exclusivity period than other drugs. As a result, many payers are turning to biosimilars, which present a major opportunity for savings in health care costs and can potentially create headroom for new expensive drugs in the pipeline. It is estimated that the utilization of biosimilars could reduce direct spending by $54 billion between 2017 and 2026.
 
Although less than 2% of Americans use biologics, they represent 40% of total spending on prescription drugs, stated Scott Gottlieb, MD, commissioner of the FDA. To maintain a commitment to reducing health care costs, the FDA released the Biosimilars Action Plan on July 18, 2018. This plan aims to stimulate and improve the biosimilar marketplace in the United States, while mitigating competition within the industry.
 
What is a biosimilar?
A biosimilar is a complex biological product that is produced in a living system, which makes it more complicated to manufacture compared with a product that is chemically synthesized. The FDA specifically defines a biosimilar as a biological product that is highly similar to, and has no clinically meaningful differences from, an existing FDA-approved reference product.
 
Cutting edge technology is utilized to compare molecular characterization (ie, purity, chemical structure, bioactivity) between the proposed biosimilar and reference product. Although minor variances are acceptable, the FDA mandates that the proposed biosimilar is highly similar to the reference product.
 
Because there is some residual uncertainty that remains about how the biosimilar product performs in body, pharmacokinetic studies are employed so that a manufacturer can demonstrate that the proposed biosimilar has no clinical meaningful differences from the reference product in terms of safety and efficacy.
 
From a clinical perspective, practitioners and clinicians have expressed their concerns related to the pharmaceutical quality, safety, and interchangeability of the biosimilar in relation to the reference product.
 
For extrapolated indications, there are uncertainties of clinical efficacy and safety for which there are no formal clinical studies.
 
“There is an expectation that when [the] FDA approves as product, it will work the same way in the body, whether they take the reference product or they take the biosimilar,” Leah Christl, PhD, associate director for Therapeutic Biologics and lead of the Office of New Drugs Therapeutic Biologics staff at the FDA Center for Drug Evaluation and Research (CDER), said in a press release.
 
What regulatory guidance is in place for biosimilars?
The Biologics Price Competition and Innovation Act of 2009 (BPCIA) was signed into law in 2010, which created an abbreviated licensure pathway for biological products shown to be biosimilar to, or interchangeable with, an FDA-licensed reference product.
 
An interchangeable product is a biosimilar that meets additional requirements based on further evaluation. Products are deemed interchangeable if they produce the same clinical result as the reference product in any given patient.
 
Manufacturers must provide data to evaluate the safety and efficacy of alternating or switching between the reference product and interchangeable product if it is administered to a patient more than once. To date, no biosimilars have been approved as interchangeable, as the FDA has yet to specify what data are needed to demonstrate a similar clinical result.
 
When 2 generic drugs are proven to be bioequivalent, they are considered to be interchangeable with the reference product and with other generics; however, this school of thought does not hold true with biosimilars. If 2 biosimilars are developed and do not have identical quality attributes, they cannot be classified as interchangeable without additional clinical data indicating otherwise.
 
If a biosimilar is not deemed to be interchangeable, it may not be automatically substituted for the prescribed branded product. More specifically, a physician must specifically prescribe the biosimilar if it is not interchangeable.
 
In 2014, the FDA released the Purple Book: Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations, which is split into products approved by the Center for Biologics Evaluation and Research and CDER. The Purple Book includes the date the biological product was licensed, whether the product was reviewed for reference product exclusivity, date of exclusivity expiry, and it provides information regarding the interchangeability of products.
 
The regulation of biosimilars raises new issues for both state and federal policymakers.
Currently, 45 states have approved legislation surrounding state standards for biosimilar substitution. Alabama, Arkansas, Mississippi, and Oklahoma have filed for legislation but have not yet received approval.
 
The FDA is lagging behind the European Union Commission’s adoption of biosimilars, as the European biosimilar market continues to expand at a rapid pace with over 40 biosimilar products across 15 different biologic classes. Since 2005, the biosimilar regulatory framework in Europe has been put into practice through the Committee for Medicinal Products for Human Use, which is governed by the European Medicines Agency.
 
More than ever, the FDA needs to provide guidance and more detailed governance to streamline the approval process and reduce the imbalance of biosimilar approvals. The BPCIA set up an abbreviated biosimilar regulatory pathway and a unique litigation framework for resolved related patent disputes.
 
As more biosimilars are brought to market, the number of patent litigation cases continues to increase. Litigation is the primary culprit for delaying market access of biosimilars.
 
What is the Biosimilars Action Plan?
On July 18, 2018, the FDA released a Biosimilars Action Plan (BAP), which strategically aims to balance innovation and competition amongst the biosimilar market. This plan “applies many of the lessons learned from our experience with generic drugs to accelerate biosimilar competition,” Gottleib said on the day that the plan was unveiled. The plan is focused on four key areas: (1) improving the efficiency of the biosimilar and interchangeable product development and approval process; (2) maximizing scientific and regulatory clarity for biosimilar product development community; (3) developing effective communications to improve understanding of biosimilars among patients, clinicians, and payers; and (4) supporting market competition by reducing gaming of FDA requirements or other attempts to unfairly delay competition.
 
During the announcement of the release of the long-awaited BAP, Gottleib announced, “And so, we need to adopt a different approach to paying for these drugs. An ideal system would reimburse biologics in a competitively bid scheme, where we could take full advantage of the multi-source competition.”
 
In the United States, the current payment system and reimbursement models were designed in a single-source system, where there was limited biologics in a therapeutic category and a lack of competition. Today, there are a host of biologics in each therapeutic category, spawning competition among many therapies targeting the same disease.
 
The FDA commissioner identified litigation for delaying market access of biosimilars among the reasons for the absence of competition. Additional factors that have prevented the entry of approved biosimilars include patents, rebates, and previously established contracts.


“Sometimes it feels as if we’re seeing the biosimilars version of ‘Groundhog Day,’ with brand drug makers replaying many of the same tactics, and all of us being too susceptible to many of the same misconceptions about biosimilars’ safety and efficacy relative to originator biologics,” Gottlieb said.
 
“But we’re not going to play regulatory whack-a-mole with companies trying to unfairly delay or derail the entry of biosimilar competitors. We’re not going to wait a decade or more for robust biosimilar competition to emerge,” he added.
 
Additionally, Gottleib said that biosimilar manufacturers may remove themselves from the space if they are unable to launch biosimilars due to a litigation holdup.
 
There’s no better time than now. FDA guidance is essential to encourage biosimilar adoption. The regulations must be instituted in order for manufacturers to bring their biosimilar to market in an effort to drive down costs.
 
Gottleib added, “The higher costs, and longer timelines, required to develop biosimilars relative to generics means that these delaying tactics can make it uneconomical for biosimilar sponsors to postpone entry for extended periods of time. I’m worried that the biosimilar manufacturers may pull out of these endeavors altogether if the brand drug makers are able to lock up markets even in cases where there’s a fully interchangeable competitor.”9
 
About the Author
Christa Eans earned her Bachelor of Science in Pharmaceutical Sciences and Doctor of Pharmacy degrees from the University of Pittsburgh. She is currently enrolled in the Master of Science in Pharmacy Business Administration (MSPBA) 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. Christa has spent the last 5 years working in Specialty Pharmacy, initially as a clinical pharmacist and most recently as the Manager of Clinical Programs. Christa is credentialed as a HIV Pharmacist (AAHIVP) through the American Academy of HIV Medicine.