The US Food and Drug Administration (FDA) today finalized three long-sought guidance documents outlining its expectations for near-exact copies of existing biological drugs known as biosimilars.

Background

The trio of guidance documents had first been released in draft form for comment in February 2012, and were the first policy documents to be released by FDA after the 2010 passage of the Biologics Price Competition and Innovation Act (BPCI)under the Patient Protection and Affordable Care Act (PPACA/Obamacare).

Now, more than three years later, FDA has finalized the same three guidance documents:

• Guidance for Industry - Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009
• Guidance for Industry - Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product
• Guidance for Industry Scientific Considerations in Demonstrating Biosimilarity to a Reference Product

Understanding the BPCI

The first guidance is a question-and-answer document outlining how FDA interprets the BPCI, including its provisions on exclusivity, biosimilarity and interchangeability.

The guidance outlines many high-level expectations for biosimilar products, including:

• Biosimilars may be formulated differently than the drug they reference in an application, but must be supported by data indicating that such differences are minor and do not result in "meaningful differences" in safety, purity and potency.
• Differences in the delivery device or container system may also be acceptable as long as differences in the delivery do not result in clinically meaningful differences and do not employ a different route of administration.
• A biosimilar product may be approved for some of the strengths for which a reference product has obtained approval. It does not need to obtain licensure for all strengths.
• Sponsors may rely on comparative animal or clinical data using a non-US-licensed product to support an indication of biosimilarity. "However, as a scientific matter, analytical studies and at least one clinical pharmacokinetic (PK) study and, if appropriate, at least one pharmacodynamic (PD) study, intended to support a demonstration of biosimilarity must include an adequate comparison of the proposed biosimilar product directly with the US-licensed reference product unless it can be scientifically justified that such a study is not needed," FDA added.

Quality Considerations

A second document explains the "quality considerations" companies need to take into account when attempting to demonstrate biosimilarity between a biosimilar product and its reference product.

The guidance can almost be summarized in a sentence, helpfully supplied by FDA on page six of the guidance document:

"Sponsors should use appropriate analytical methodology that has adequate sensitivity and specificity to detect and characterize differences between the proposed product and the reference product."

In plain terms: Because biosimilar products are always going to have minor differences relative to the products they reference, FDA is primarily concerned with understanding the effects those differences might have on the safety, efficacy, potency and quality of the biosimilar product.

Regulators go on to explain in the guidance document that companies are required by law "to include data supporting the analytical similarity of the proposed biosimilar product to the reference product." The rationale for the assessment should be "clearly described" in the submission, FDA added.

The guidance goes into great detail regarding the various quality factors sponsors should take into account when characterizing a biosimilar product.

Scientific Considerations

Finally, the third guidance document explains FDA's recommended approach for demonstrating biosimilarity using scientific data.

"As set forth in the PHS Act, data derived from analytical studies, animal studies, and a clinical study or studies are required to demonstrate biosimilarity unless FDA determines an element unnecessary," FDA explains in the guidance.

So what will it take it illustrate, scientifically, that a product is biosimilar to its reference product?

"As a scientific matter, analytical studies and at least one clinical PK study and, if appropriate, at least one PD study, intended to support a demonstration of biosimilarity for purposes of section 351(k) of the PHS Act must include an adequate comparison of the proposed biosimilar product directly with the U.S.-licensed reference product unless it can be scientifically justified that such a study is not needed," FDA wrote.

FDA encourages sponsors to utilize what it calls a "stepwise approach" to demonstrate biosimilarity. "At each step, the sponsor should evaluate the extent to which there is residual uncertainty about the biosimilarity of the proposed product and identify next steps to try to address that uncertainty," regulators explained.

FDA said it will consider the "totality of the evidence" when assessing a sponsor's evidence of biosimilarity.

As with the second guidance document, the remainder of this guidance contains extensive information regarding how sponsors can use scientific methods to demonstrate biosimilarity.