FDA Issues New Draft Guidance on Biosimilars

March 27, 2017Articles The National Law Journal

The Biologics Price Competition and Innovation Act of 2009, enacted as part of the Affordable Care Act, established a uniform process for approval of "generic" versions of biopharmaceuticals previously approved by the U.S. Food and Drug Administration. The BPCIA also set forth conditions for regulatory exclusivity and a streamlined process for any patent litigation.

But the law was nearly useless for companies hoping to market these so-called biosimilars because there was no FDA guidance on how to qualify as a drug that pharmacists are permitted to substitute for the brand name product.

Until now.

In January 2017, the FDA issued draft guidance titled "Considerations in Demonstrating Interchangeability With a Reference Product." In it, the agency outlines the nature and quality of the evidence applicants should expect the FDA to demand before making a finding of interchangeability for a biosimilar.

Biopharmaceuticals can be vaccines, antibodies, cellular components or other proteins. They differ from standard pharmaceuticals principally in that they are harvested from biological sources, such as a cell culture, rather than chemically synthesized.

Since they originate from living sources, its structural complexity is far greater than standard pharmaceuticals (potentially millions of atoms compared to dozens), and their composition is ultimately dependent on the biological source. It is virtually impossible, therefore, to generate a "generic" biopharmaceutical that is structurally identical, as is routine for standard pharmaceuticals once the chemical structure is known.

Because of the practical impossibility in creating "bioequivalent" biopharmaceuticals, the determination of "biosimilarity" under the BPCIA requires a showing of both high structural similarity and high functional similarity. For FDA approval, the applicant must show that the biosimilar "is highly similar to the reference product notwithstanding minor differences in clinically inactive components" and that "there are no clinically meaningful differences between the [biosimilar] and the reference product in terms of the safety, purity and potency of the product."

Biosimilarity is the minimum showing required for FDA approval. It may result in approval to market, but it will not result in regulatory exclusivity under the BPCIA, which is limited to the first interchangeable biosimiliar. Interchangeability requires a showing that the biosimilar "can be expected to produce the same clinical result as the reference product in any given patient" and that "for a [biosimilar] that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the [biosimilar] and the reference product is not greater than the risk of using the reference product without such alternation or switch."

Interchangeability is not the same as "bioequivalence." Beyond regulatory exclusivity, interchangeability additionally allows for "point of sale" substitutions by a pharmacist without intervention of the prescribing doctor. Thus, the potential benefits of "interchangeability" are substantial.

There are currently four FDA-approved biosimilars: Sandoz's Zarxio, referencing Amgen's Neupogen (filgrastim); Pfizer's Inflectra, referencing Janssen's Remicade (infliximab); Sandoz's Erelzi, referencing Amgen's Enbrel (etanercept); and Amgen's Amjevita, referencing AbbVie's Humira (adalimumab). None have been deemed "interchangeable" by the FDA, and thus may not be substituted by a pharmacist.


In the January guidance, the FDA outlines four key points for biosimilar sponsors:

• The more complex the product, the more comparative and functional characterization will be necessary to support a demonstration of interchangeability. This does not focus just on structural complexity, but also the mechanism of action with target receptor(s)/in vivo effects on biological pathway(s). The guidance emphasizes demonstrating "fingerprint-like analytical similarity" between the biosimilar and the reference product.

• For biosimilars that are intended to be administered to an individual more than once, the FDA expects the sponsor to conduct a "switching study" or studies to illustrate that there is no diminished risk in terms of safety or efficacy in alternating or switching between the biosimilar and the reference product. For those that are not intended to be administered more than once, the FDA expects switching studies would "generally not be needed." However, the guidance goes on to state that, in such instances, the sponsor should provide justification for not needing a switching study. Best practice for a sponsor may be to include a switching study even in such circumstances. Furthermore, the guidance makes clear that a switching study should use only "U.S.-licensed" (FDA approved) reference products; biosimilarity studies otherwise do not require (but as best practice, should probably use) U.S.-licensed reference products.

• Biosimilars using reference products with known issues relating to immunogenicity will require "more data" to support interchangeability than those without. The guidance does not explicitly define what "more data" comprises, but suggests in such circumstances, the sponsor will need to present post-marketing data before interchangeability can be demonstrated.

• However, post-marketing data without corresponding data derived from an appropriately designed, prospective, controlled switching study or studies, generally is not sufficient to show interchangeability. This is one of the few bright-line distinctions made in the guidance.

The guidance also sets forth protocols for integrated study designs for sponsors interested in showing biosimilarity along with interchangeability. For more complex biosimilars, it appears that the FDA will still require post-marketing data before a determining interchangeability.

Finally, the guidance describes at length the delivery device and labeling comparison (termed "presentation" in the guidance) between the biosimilar and the reference product.

It appears that the FDA will tolerate only "minor" design differences in product presentation, and only under limited circumstances. The agency suggests use of "comparative use human factor studies" (set forth in Appendix A of the guidance) in evaluating whether or not "minor" design differences will lead to a negative outcome.

Ultimately, while the guidance sets forth a number of helpful recommendations, the FDA advises sponsors not to rely solely on the guidance, but rather to directly consult the FDA throughout the process.

Reprinted with permission from the March 27 issue of The National Law Journal. (c) 2017 ALM Media Properties, LLC. Further duplication without permission is prohibited. All rights reserved.