The Biologics Price Competition and Innovation (BPCI) Act of 2009 was enacted as part of the Patient Protection and Affordable Care Act to establish an abbreviated pathway for the licensure by Food and Drug Administration (FDA) of biological products demonstrated to be biosimilar to or interchangeable with a FDA-licensed reference product. We at the BRIC Wall Blog decided to review the current status of biosimilars in the U.S.

FDA Guidances

Since the BPCI Act was signed into law on March 23, 2010, the FDA has issued six guidances relating to biosimilars or reference biological products. These guidances are:

1.  Guidance for Industry on Biosimilars: Q & A’s Regarding Implementation of the BPCI Act of 2009 – issued February 9, 2012.

2.  Scientific Considerations in Demonstrating Biosimilarity to a Reference Product – issued February 9, 2012.

3.  Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product – issued February 9, 2012.

4.  Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants – issued March 29, 2013.

5.  Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product (Clinical Pharmacology Guidance) – issued May 13, 2014.

6.  Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the PHS Act (Exclusivity Guidance) – issued August 4, 2014.

A detailed examination of the Clinical Pharmacology Guidance and Exclusivity Guidance, the two guidances released in 2014, is provided below.

Clinical Pharmacology Guidance

Clinical pharmacology studies are a critical part of demonstrating biosimilarity and are used to support a demonstration that there are no clinically meaningful differences (in terms of safety, purity and potency) between a proposed biosimilar product and a reference product. The Clinical Pharmacology Guidance provides information for proposed biosimilar products for which pharmacokinetic (PK) and pharmacodynamic (PD) data are required as part of the stepwise approach in developing the data and information necessary to support a demonstration of biosimilarity. Specifically, this guidance discusses concepts related to clinical pharmacology testing for biosimilar products, approaches for developing the appropriate clinical pharmacology database and the utility of modeling and simulation for designing clinical trials.

According to the guidance, in the step-wise assessment of biosimilarity, extensive and comparative structural and functional studies (such as, bioassays, binding assays, and studies of enzyme kinetics) should be performed to evaluate whether the proposed biosimilar product and the reference product are highly similar. The guidance describes four possible assessments of biosimilarity. These are:

1.  Highly similar with fingerprint-like similarity: Under this assessment, the proposed biosimilar product meets the statutory standard for analytical similarity based on integrated, multi-parameter approaches that are extremely sensitive in identifying analytical differences. The result of the analysis permits a high level of confidence in the analytical similarity of the proposed biosimilar and the reference product. Thereupon, under this assessment, it is appropriate for the sponsor to use a more targeted and selective approach to conduct animal and/or clinical studies to resolve residual uncertainty and support a demonstration of biosimilarity. This is the gold standard.

2.  Highly similar:   Under this assessment, the proposed biosimilar product meets the statutory standard for analytical similarity. Specifically, the results of the comparative analytical characterization permit high confidence in the analytical similarity of the proposed biosimilar and the reference product, and it is appropriate for the sponsor to conduct targeted and selective animal and/or clinical studies to resolve residual uncertainty and support a demonstration of biosimilarity.

3.  Similar: Under this assessment, information is needed to determine if the proposed biosimilar product is highly similar to the reference product. Additional analytical data or other studies are necessary to determine if the observed differences are within an acceptable range to consider the proposed biosimilar product to be highly similar to the reference product. The example provided in the guidance is glycosylation. Glycosylation plays an important role in the PK of certain protein products and manufacturing process conditions may impact glycosylation. Comparative PK and PD studies of the proposed biosimilar product and the reference product would be helpful in resolving whether some of the differences in glycosylation identified in the analytical studies are within an acceptable range to consider the proposed biosimilar product to be highly similar to the reference product.

4.  Not similar: Under this assessment, differences in the results of the analytical characterization may lead to an assessment of “not similar” for the proposed biosimilar product. In this instance, further development under the 351(k) regulatory pathway (namely, the regulatory pathway for biosimilars) is not recommended unless, for example, modifications are made to the manufacturing process for the proposed biosimilar product that are likely to lead to a highly similar biological product.

According to the guidance, the outcome of the comparative analytical characterization provides information to the sponsor regarding the next steps needed to demonstrate biosimilarity.

Exclusivity Guidance

The Exclusivity Guidance describes how the FDA will determine the date of first licensure of a reference product and the types of information reference product sponsors should provide to facilitate FDA’s determination of the date of first licensure for their products. The guidance states that in most instances, the date of first licensure will be the initial date the particular product at issue was licensed in the U.S. However, the 12-year exclusivity period does not apply if the licensure is for:

1.  A supplement for the biological product that is the reference product; or

2.  A subsequent application filed by the same sponsor or manufacturer of the biological product (or a licensor, predecessor in interest, or other related entity) for:

a.  A change (not including a modification to the structure of the biological product) that results in a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device, or strength; or

b.  A modification to the structure of the biological product that does not result in a change in safety, purity, or potency.

Moreover, according to the guidance, the burden is on the sponsor to demonstrate that a new licensure meets the standards for exclusivity.

For biological products that may or may not be entitled to reference product exclusivity, the FDA suggests a four-step process for sponsors to provide certain relevant information.  Specifically, the FDA suggests that sponsors provide the following:

1.  A list of all the licensed biological products that are structurally related to the biological product that is the subject of the 351(a) application (namely, a biologics license application (BLA)) being considered.  This includes products that share the same molecular target or have some of the same principal molecular features.  Where molecular targets have not been defined, the list should include products that share the narrowest target that can be characterized (this may be a pathway, celltype, tissue or organ system).  If a sponsor determines there are no licensed products that fall into these categories, it must provide an “adequate justification” to support this assertion.

2.  Of the licensed products from item 1, a list of those which the sponsor or one of its affiliates, including any licensors, predecessors in interest, or related entities, are the current or previous license holder.  The term “licensors” is defined broadly to include “any entity that has granted the sponsor a license to market the biological product, regardless of whether such license is exclusive”. This definition includes entities that continue to retain rights to develop, manufacture, or market the biological product, and/or rights to intellectual property that covers the biological product. The term “predecessors in interest” has been interpreted by FDA to mean an entity (such as a corporation) that the sponsor has taken over, merged with, or purchased, or from which the sponsor has purchased all rights to the drug (namely, the reference product). Additionally, the FDA has construed the term “predecessor in interest” to include an entity which has granted to the sponsor exclusive rights to a new drug application or the data upon which exclusivity is based, which may include licensors, assignors, and joint venture partners, depending on the circumstances of a case. Moreover, the FDA will consider any entity that the sponsor has taken over, merged with, or purchased or that has granted the sponsor exclusive rights to market the biological product under a BLA application, or had exclusive rights to the data underlying the application to be a predecessor in interest. 

The BPCI Act does not define the term “other related entity”. Nonetheless, the FDA generally considers a sponsor to be a “related entity” if: (i) either entity owns, controls or has the power to own or control the other entity (either directly or thorough one or more other entities) or (ii) the entities are under common ownership or control. According to the guidance, the FDA expects to consider not only ownership and control of the investigational new drug application (IND) and BLA, but also the level of collaboration between the entities during the development of the program as a whole.

3.  A description of the structural differences between the proposed biological product and any products identified in item 2.  For protein products, sponsors are asked to discuss “differences in amino acid sequence, glycosylation patterns, tertiary structures, post-translational events, infidelity of translation or transcription, differences in glycosylation patterns or tertiary structure, and differences in biological activities.”. 

4.  Evidence of the change in safety, purity, and/or potency between the proposed biological product and any products identified in item 2. Such evidence should include a description of how the structural differences identified in item 3 relate to changes in safety, purity and/or potency.

The FDA encourages sponsors to provide this information at the time of 351(a) application is submitted (as correspondence to the application) or as an amendment to an application.

What is in a (biosimiliar) name?

There have been several reports that the FDA has completed a draft guidance document on the naming of biosimilar products. However, the reason the draft guidance has not yet been released is a delay by the Department of Health and Human Services in completing its review of the document. In fact, in August 2014, two of the Senate’s high ranking legislators on healthcare, Lamar Alexander (R-TN) and Orrin Hatch (R-UT), called for the release of FDA’s biosimilar naming guidance. Unfortunately, despite the Senators urging, the guidance has still not yet been released and the time table for release is unknown.

The Purple Book

In September 2014, the FDA began publishing the “Purple Book”, the biologic counterpart to the Orange Book for “small molecule” drugs. The book is split into two parts, one for products approved by the Center for Drug Evaluation and Research (CDER) and the other for products approved by the Center for Biologics Evaluation and Research (CBER). Information included in the Purple Book includes:

1.  BLA number;

2.  Product (Proper) Name;

3.  Proprietary Name;

4.  Date of Licensure;

5.  Date of First Licensure;

6.  Reference product Exclusivity Expiry Date;

7.  Interchangeable or biosimilar; and

8.  Withdrawn.

Unfortunately, the published information presently contained in the Purple Book is not very complete. Specifically, the date of first licensure and the date of expiration of product exclusivity is provided for only a very small number of products. Also, unlike the Orange Book, the Purple Book does not list any patent information.

Awaiting Approval

As readers may recall, in July 2014, Sandoz announced that it had filed a 351(k) application for a biosimilar version of filgrastim. Sandoz’ biosimilar of filgrastim is marketed in more than 40 countries under the brand name ZARZIO®. Approximately one month later, Celltrion announced the filing of its 351(k) application for a biosimilar of infliximab (Remicade®). The industry is anxiously awaiting news regarding the approval of these products.