Clinical UM Guideline


Subject: FDA-Approved Biosimilar Products
Guideline #:  CG-DRUG-64 Publish Date:    12/27/2017
Status: Reviewed Last Review Date:    11/02/2017


This document provides clinical criteria for review of FDA-approved biosimilar products. A biosimilar product is a biological product that is highly similar to an already-Food and Drug Administration (FDA)-approved biological product, known as a reference or originator product. In order to gain FDA approval as a biosimilar, the product must show it has no clinically meaningful differences in terms of safety and efficacy from the reference product; only minor differences in clinically inactive components are allowable. Biological products are generally derived from a living organism. They can come from many sources, including humans, animals, microorganisms or yeast.

Note: For additional information on review of clinically equivalent cost effective criteria for products addressed in CG-DRUG-64, please refer to CG-ADMIN-02 Clinically Equivalent Cost Effective Services - Targeted Immune Modulators.

Clinical Indications

Use of a biosimilar product is considered medically necessary when both of the following conditions (A) and (B) are met (where condition (B) is not applicable, only criterion (A) must be met):

  1. The product is approved by the FDA as a biosimilar to a FDA-approved reference product. If the biosimilar product does not meet this threshold criteria, it is not medically necessary; and
  2. The biosimilar product must also, if applicable, meet the medically necessary criteria of (1) a Company Medical Policy or Clinical Utilization Management (UM) Guideline specific to the reference product when available; or (2) in the absence of a Company Medical Policy or Clinical UM Guideline specific to the reference product, for off-label use (based on the indication(s) listed in the reference product label), pursuant to the criteria of CG-DRUG-01 Off-Label Drug and Approved Orphan Drug Use, and the position statement(s) in any such specific Medical Policy or the clinical indications in any such specific Clinical Guideline or in CG-DRUG-01, as applicable, will apply.
Clinically Equivalent Cost Effective Agents

Note: When a biosimilar or reference product is determined to be medically necessary based on the clinical criteria above, the benefit plan may have in addition a medical necessity criterion that the treatment be cost effective. When such language exists, the benefit plan may determine whether the biosimilar or the reference product is covered.

A list of the cost effective biosimilar or reference products is available here.

In benefit plans where there is a requirement to use a cost effective biosimilar or reference product, requests for a biosimilar or reference product(s) that is not cost effective may be approved when the following criteria are met:

  1. The individual has had a trial of and is intolerant to one cost effective agent; or
  2. For the prescribed indication, the cost effective agent(s) is/are not FDA-approved or does/does not meet the off-label drug use criteria of CG-DRUG-01 Off-Label Drug and Approved Orphan Drug Use.

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.




All biosimilar product codes including, but not limited to:


Unclassified biologics [when specified as etanercept-szzs (Erelzi), adalimumab-atto biosimilar (Amjevita), or adalimumab-adbm (Cyltezo), or bevacizumab-awwb (Mvasi)]


Injection, filgrastim (G-CSF), biosimilar, 1 microgram [filgrastim-sndz (Zarxio)]


Injection, infliximab, biosimilar, 10 mg [infliximab-dyyb (Inflectra, Pfizer/Hospira modifier -ZB); infliximab-abda (Renflexis, Merck/Samsung Bioepis modifier -ZC)]

Note: See the indicated Reference Document for medical necessity diagnosis coding for those biosimilar products which have a reference product addressed in a specific document.

Discussion/General Information

In traditional small molecule, chemically synthesized drugs, completely identical generic versions can be manufactured with relative ease. Zelenetz and colleagues (2011) indicated that biologic products are not identical to their counterparts noting:

…because biologics are complex products produced by living systems, they will inherently exhibit some physiochemical differences in addition to the varying production processes that will also modify the products (e.g., purification methods), and therefore biosimilars can be close or “similar” to the innovator products but will not be identical.

In 2010, the Public Health Service Act (PHS Act) was amended to allow for an abbreviated licensure pathway for biological products that are considered “biosimilar” to or “interchangeable” with a current FDA-licensed biological reference product. The FDA has provided the following definitions:

A biosimilar product is a biological product that is approved based on a showing that it is highly similar to an FDA-approved biological product, known as a reference product, and has no clinically meaningful differences in terms of safety and effectiveness from the reference product. Only minor differences in clinically inactive components are allowable in biosimilar products.

The abbreviated pathway for biological products means that the biosimilar products can be approved by the FDA based upon less than a full set of preclinical and clinical data because of a reliance on the safety and efficacy data of the reference drug. The goal of the testing of a biosimilar product is to determine whether the product is biosimilar to the reference product. The goal is not to independently determine the safety and efficacy of the biosimilar. The pathway includes analytical structural and functional testing conducted on the proposed biosimilar and the reference product to determine whether the biosimilar product is highly similar to the reference product. The abbreviated pathway is meant to avoid redundant clinical testing, potentially shorten the timeline to product approval, and increase the therapeutic options for individuals.

The FDA recommends a stepwise approach to demonstrating biosimilarity including structural analyses, functional assays, animal testing, comparative human pharmacokinetic (PK) and pharmacodynamics (PD) studies, and a clinical immunogenicity assessment. Any differences, such as safety, purity or potency (safety and effectiveness), which are identified during the testing process much be evaluated to determine potential impact. Any concerns raised during the initial testing may be addressed in a comparative clinical study which should be designed to investigate whether there are clinically meaningful differences between the proposed biosimilar product and the reference product (FDA, 2015).

The NCCN Biosimilar work group consensus published a number of recommendations regarding the development, testing, use and education related to biosimilar products including the following statements related to the approval pathway and the standardization with the reference product:

Company Medical Policy or Clinical UM Guideline Biosimilar/Reference Table

Biosimilar Product

Reference Product

Reference Document



adalimumab (Humira®)

CG-DRUG-65 Tumor Necrosis Factor Antagonists



adalimumab (Humira®)

CG-DRUG-65 Tumor Necrosis Factor Antagonists



bevacizumab (Avastin®)

DRUG.00028 Intravitreal Treatment for Retinal Vascular Conditions


CG-DRUG-68 Bevacizumab (Avastin®) for Non-Ophthalmologic Indications



etanercept (Enbrel®)

CG-DRUG-65 Tumor Necrosis Factor Antagonists



filgrastim (Neupogen®)

CG-DRUG-16 White Blood Cell Growth Factors



infliximab (Remicade®)

CG-DRUG-65 Tumor Necrosis Factor Antagonists



infliximab (Remicade)

CG-DRUG-65 Tumor Necrosis Factor Antagonists

*Table might not be inclusive of all biologics


Peer Reviewed Publications:

  1. Ben-Horin S, Vande Casteele N, Schreiber S, Lakatos PL. Biosimilars in inflammatory bowel disease: facts and fears of extrapolation. Clin Gastroenterol Hepatol. 2016; 14(12):1685-1696.
  2. Declerck P, Danesi R, Petersel D, Jacobs I. The Language of Biosimilars: Clarification, Definitions, and Regulatory Aspects. Drugs. 2017; 77(6):671-677.
  3. Dos Reis C, Teixo R, Mendes F, Cruz RS. Biosimilar medicines - Review. Int J Risk Saf Med. 2016; 28(1):45-60.
  4. Jacobs I, Ewesuedo R, Lula S, Zacharchuk C. Biosimilars for the treatment of cancer: a systematic review of published evidence. BioDrugs. 2017; 31(1):1-36.
  5. Ventola CL. Biosimilars: part 1: proposed regulatory criteria for FDA approval. P T. 2013; 38(5):270-287.
  6. Ventola CL. Biosimilars: part 2: potential concerns and challenges for p&t committees. P T. 2013; 38(6):329-335.
  7. Ventola CL. Evaluation of Biosimilars for Formulary Inclusion: Factors for Consideration by P&T Committees. P T. 2015; 40(10):680-689.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. American Academy of Dermatology (AAD). Position Statement on Generic Therapeutic & Biosimilar Substitution. Amended August 3, 2013. Available at: Accessed on October 3, 2017.
  2. American College of Rheumatology (ACR). American College of Rheumatology Position Statement: Biosimilars. April 2016. Available at: Accessed on October 3, 2017.
  3. American Society of Clinical Oncology (ASCO) Policy Brief. Biosimilars. December 2015. Available at: Accessed on October 3, 2017.
  4. Holmes DR Jr, Becker JA, Granger CB, et al; American College of Cardiology Foundation Clinical Quality Committee. ACCF/AHA 2011 health policy statement on therapeutic interchange and substitution: a report of the American College of Cardiology Foundation Clinical Quality Committee. J Am Coll Cardiol. 2011; 58(12):1287-1307.
  5. U.S. Food & Drug Administration (FDA).
  6. World Health Organization (WHO). Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs). October 2009. Available at: Accessed on October 3, 2017.
  7. Zelenetz AD, Ahmed I, Braud EL, et al. NCCN Biosimilars White Paper: regulatory, scientific, and patient safety perspectives. J Natl Compr Canc Netw. 2011 Sep;9 Suppl 4:S1-22.
Websites for Additional Information
  1.  U.S. Food & Drug Administration (FDA). Information for Consumers (Biosimilars). Updated August 27, 2015. Available at:
    . Accessed on October 3, 2017.
  2. U.S. Food & Drug Administration (FDA). Information on Biosimilars. Updated on May 10, 2016. Available at:
    . Accessed on October 3, 2017.

adalimumab-adbm (Cyltezo)
adalimumab-atto (Amjevita)
bevacizumab-awwb (Mvasi)
etanercept-szzs (Erelzi)
filgrastim-sndz (Zarxio)
infliximab-abda (Renflexis)
infliximab-dyyb (Inflectra)

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.







Medical Policy & Technology Assessment Committee (MPTAC) review. The document header wording updated from “Current Effective Date” to “Publish Date.” Revised name of related policy DRUG.00002 Tumor Necrosis Factor Antagonists to CG-DRUG-65 with same title in the discussion section. Updated References and Websites sections.



Updated Discussion and Index sections adding new FDA approved biosimilars adalimumab-adbm and bevacizumab-awwb and a note referring to CG-ADMIN-02. Updated Coding with new HCPCS modifier for Renflexis effective 10/01/2017.



Updated Coding, Discussion and Index sections adding new FDA approved biosimilar infliximab-abda.



MPTAC review. Changed title of the “Preferred Agents” section to “Clinically Equivalent Cost Effective Agents.”



MPTAC review.



Hematology/Oncology Subcommittee review. Initial document development.