Q&A with Edward Li, PharmD, MPH, BCOP

Pharmacy Purchasing & Products: How should health systems evaluate biosimilars for formulary inclusion?
Edward Li: To begin, the pharmacy or formulary committee must establish the intended indications for each biological molecule in question, whether it is a reference product or a biosimilar. With regard to biosimilars, the committee then should review the data package that was submitted to the FDA, which includes comparability exercises that demonstrate the compound’s biosimilarity to its reference product. After reviewing all of the relevant product literature, the committee then must consider the end use of the biosimilar product. It is important to note that the comparative clinical studies on biosimilarity submitted to the FDA cover only on-label indications and that FDA might have used these data to extrapolate from one indication to another. Biologics often are used for on-label and off-label purposes. If the pharmacy and therapeutics (P&T) committee or the formulary committee determines that a biologic reference product is being used regularly for off-label indications, they also must decide whether to use a biosimilar in the same manner.

Therefore, P&T committees should consider, as the FDA does, the totality of the evidence, including studies that focus on comparing the molecule’s structure and function, pharmacokinetics (PK) and pharmacodynamics (PD), and safety and efficacy to the reference product. The group then must extrapolate the findings from studies involving on-label indications and apply them to potential off-label uses.

PP&P: Can you share some insight into how the FDA’s biosimilar approval pathway works?
Li: As mentioned, the FDA bases the approval of biosimilars on what they call the totality of evidence in five domains, which lay the foundation for the comparability exercise. Prior to FDA approval, the candidate biosimilar undergoes an extensive and rigorous comparison to the reference product. Some clinicians worry that biosimilars will undergo only placebo-controlled studies, but this is not true. All biosimilars submitted to the FDA will be compared to the reference product in question.

Comparability exercises are based on five domains:

Structural and Functional Characterization
The biosimilar sponsor must establish the structure of the biosimilar, characterize the molecule, and identify impurities, etc, in an effort to show that the structure and function of the molecule are pharmacologically comparable in in vitro capabilities.

Animal Studies
The biosimilar sponsor may submit data from animal studies to demonstrate biosimilarity, unless the FDA thinks they are unnecessary. For example, animal toxicity studies usually can be performed when there is residual uncertainty regarding the comparability of the molecule structure and function to the reference product.

Human PK/PD Data
The FDA reviews the PK and PD of the biosimilar using the same route of administration (eg, subcutaneous, intravenous) as that used by the reference product.

Clinical Immunogenicity
The immunogenicity assessment often is performed in concert with the human PK/PD review or during the safety and efficacy studies. All biologics carry some risk of immunogenicity, but the FDA’s goal is to ensure that the risk associated with the biosimilar is no greater than that associated with the reference biologic.

Safety and Efficacy
This goal of this process is not to establish whether the biosimilar is effective for its indication (the biological molecule has already been established to be safe and effective by the reference manufacturer); rather, it is a comprehensive comparability exercise to verify that the biosimilar matches the safety and efficacy established by the reference product in clinical trials, using a sensitive end point, so that should a difference exist, it would be more easily identified when evaluating that end point.

Many clinicians may be tempted to evaluate a biosimilar using only its randomized, controlled studies on safety and efficacy as the basis for their determination. While these studies are important, they do not provide a complete picture. For example, if a clinician looks solely at safety and efficacy studies, there may not be any for the indications for which the biosimilar is intended to be used. Further, the absence of such a study for an off-label indication does not necessarily mean that the biosimilar is not appropriate for that use.

This begs the most significant question regarding biosimilars: What is acceptable off-label use? In oncology, many cancer drugs are used off label, usually with support from randomized, controlled trials that indicate efficacy. However, few, if any, randomized, controlled trials for off-label indications will exist for biosimilars. Most sponsors are disinclined to invest in such studies, as they increase development costs. Thus, hospitals must determine for themselves the off-label uses for individual molecules that they feel comfortable offering, based on the available evidence. They must conduct the extrapolation assessment to off-label indications just as the FDA does for on-label indications. Hopefully, in the future, national organizations and compendia will develop guidelines that will assist in this regard.

PP&P: What is the difference between a biosimilar and an interchangeable biosimilar?
Li: Theoretically, an interchangeable biosimilar is one that has been deemed capable of being interchanged with the reference product with absolutely no clinical consequences. The primary concern when establishing interchangeability is determining whether a patient might develop neutralizing antibodies against the biosimilar. To address this, the FDA has stated that studies will be required to demonstrate that it is acceptable to switch back and forth between the reference and biosimilar with no clinical differences in efficacy and safety; however, the FDA has not yet released guidance on what these studies should look like.

Outside of definitive guidance from the FDA, some manufacturers are designing studies to attempt to demonstrate interchangeability. Biosimilar manufacturers may simply submit their studies to the FDA and see what happens.  

PP&P: How does price factor into a health system’s decision to consider switching from a reference product to a biosimilar?
Li: First, it is important to note that because health systems negotiate medication prices, the biosimilar may not always have the least expensive acquisition cost. However, it is reasonable to assume that the competition introduced by biosimilars will drive down overall biologic costs. Manufacturers of reference products may provide discounts, in certain circumstances, to retain market share. Also, they may bundle the reference product with other products, which introduces additional cost considerations. The same could be done by the biosimilar manufacturer. The point is that most facilities will consider biosimilars as an addition to, or replacement for, a reference product on a case-by-case basis in the context of the larger medication acquisition process. However, it is important to remember that each consideration should include a detailed evaluation of packaging needs, storage and handling requirements, rebates and discounts from both the reference and biosimilar manufacturers, and any other management issues attendant to switching or replacing medications.

Another element that organizations must consider is that most biologic products are administered in the outpatient setting, which has significant cost implications. Although some biologic products are inpatient-based, many others, such as infliximab and other antiinflammation biologics, erythropoiesis-stimulating agents (ESAs), and myeloid growth factors, tend toward outpatient administration with attendant reimbursement considerations, most often based on payer reimbursement policies. So, the issue is not just one of direct cost; rather, the organization must consider the margins on top of the total reimbursement for the product. From a cost perspective, the organization ultimately should seek not just the least expensive agents, but the most financially viable ones when taking into account all factors.

PP&P: Does it make sense for an organization to retain the reference product in addition to adding its biosimilar to the formulary?
Li: This decision depends on a number of factors. In the case of hospitals that work with private physician practices, as opposed to physician employees, the hospital is limited by its inability to regulate which products are prescribed by those practices, including whether the practice will use a reference biologic or a biosimilar. Given that biologics frequently are administered in the outpatient setting, prescribing variances may become common. Moreover, this underscores the issues that can arise during transitions of care. Once a patient is admitted into the hospital, a determination must be made either to continue the initial product or switch to the formulary product. Unless the reference biologic and biosimilar are deemed by the FDA to be interchangeable or thought to be interchangeable by the health system’s P&T committee, the facility is obliged to continue using the initial product to maintain continuity of care.

Ultimately, the facility needs to be cognizant of biologic utilization outside of its jurisdiction and draft a procedure to guide product-by-product utilization decisions, in order to determine biologic therapy for these scenarios.

PP&P: Can you weigh in on the controversy regarding biosimilar naming conventions?
Li: On August 27, 2015, the FDA released draft guidance detailing their proposal regarding the nonproprietary naming of biological products.¹ The guidance proposes that reference products and biosimilars have nonproprietary names, also called proper names, that share a core drug substance name. Additionally, in order to better identify each product, an FDA-designated suffix that is unique for each product should be included. This suffix would comprise four lowercase letters that do not carry any meaning. For interchangeable biological products, FDA has requested feedback from the public regarding whether the nonproprietary name should include a distinct suffix or should share the same suffix as the reference product. The proposed naming convention seeks to address two main concerns:

1. To help prevent inadvertent substitution of biological products that are not determined to be interchangeable by FDA; and
2. To support safety monitoring (ie, pharmacovigilance) of all biological products after they are on the market by making it easier to accurately track usage of biological products in all settings of care, including outpatient, hospital, and pharmacy settings.

FDA also is considering, and has requested public comment on, the benefits and challenges of other naming approaches, such as a suffix derived from the name of the license holder.

In addition to naming concerns for future biological products, it is important to consider how to address previously approved biological products that have nonproprietary names without a suffix. FDA also is seeking public comment on this topic and has issued a proposed rule to designate nonproprietary names that contain a suffix for six previously licensed biological products; each of these products is either a reference product for an approved or publicly disclosed biosimilar product application or a biological product that is either biosimilar to, or related to, one of these reference products.²

From a pharmacy perspective, FDA’s proposed approach to naming biosimilars appears prudent; prescribers and pharmacists must be able to track adverse events back to a specific product and manufacturer, and this naming convention will assist in this endeavor. However, there have been cases where health care workers either have ignored or failed to comprehend the meaning of a suffix, leading to medication errors. Also, if the FDA changes the suffix after an interchangeability designation is made, this could potentially cause confusion among clinicians.

PP&P: What education should be provided to patients regarding biosimilars?
Li: It is important to assure patients that biosimilars are high-quality products that have been extensively studied and have gone through rigorous comparability exercises.

Nevertheless, biologics should be treated similarly to narrow therapeutic index drugs. Consider patients on levothyroxine or cyclosporine, as an example; different formulations of these drugs can significantly affect therapeutic concentration, making pharmacists the arbiter of medication continuity. Likewise, if the reference product and biosimilar are not interchangeable and there are concerns with switching, then the patient should remain on the initial product, regardless of whether it is a reference or biosimilar.

Obviously, some patients will have idiosyncratic reactions to specific drugs—especially with large-molecule drugs—but such reactions are difficult, if not impossible, to foresee. From an overall patient population perspective, idiosyncrasies between a reference product and its biosimilar should occur at about the same rate.

References

1. Woodcock J and Midthun K. US Food and Drug Administration Web site. FDA Voice: Naming and Biological Products. http://blogs.fda.gov/fdavoice/index.php/2015/08/naming-and-biological-products/. Accessed October 6, 2015.
2. Federal Register. The Daily Journal of the United States Government. Designation of Official Names and Proper Names for Certain Biological Products (8/28/2015). https://www.federalregister.gov/articles/2015/08/28/2015-21382/designation-of-official-names-and-proper-names-for-certain-biological-products. Accessed October 6, 2015.

Edward Li, PharmD, MPH, BCOP, is an associate professor in the department of pharmacy practice at the University of New England College of Pharmacy. He earned his Doctor of Pharmacy degree from the Philadelphia College of Pharmacy and his Master of Public Health from the University of New England. Edward completed a pharmacy practice residency at the University of Wisconsin Hospital and Clinics and an oncology pharmacy practice residency at the University of Maryland School of Pharmacy. His research focuses on cancer pharmacoepidemiology, pharmacoeconomics, and evaluating health policy issues as they relate to oncology practice.

FDA Biosimilars Guidance Documents
(available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm290967.htm)

• Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors of Applicants (draft guidance). March 2013.
• Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product (draft guidance). May 2014.
• Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the PHS Act (draft guidance). August 2014.
• Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 (final guidance). April 2015.
• Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product (final guidance). April 2015.
• Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (final guidance). April 2015.
• Biosimilars: Additional Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 (draft guidance). May 2015.