Biologic Interchangeability Must Be for All Uses, AbbVie Says

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By John T. Aquino

Dec. 30 — The FDA should find a biologic product interchangeable with a reference product (RP) only if it's interchangeable for every approved use of the RP, AbbVie Inc. wrote the agency in a Dec. 16 citizen petition.

AbbVie also asked the Food and Drug Administration to clarify the statutory standards for establishing interchangeability and to convene a hearing to get public input on the topic.

A biosimilar is a biologic product that is approved for market by the FDA based on a showing that it is highly similar to an already approved biologic known as an RP. An interchangeable biologic product is biosimilar to an FDA-approved RP and meets additional standards for interchangeability, which would allow it to be substituted for an RP by a pharmacist without prior permission from the prescribing physician.

AbbVie said its petition was prompted by concerns about patient safety. It also appears to be related to the upcoming expiration of its patent for Humira and Amgen Inc.'s planned Humira biosimilar.

So far, the FDA has approved only one biosimilar, and has yet to issue any determinations of interchangeability, AbbVie's petition said. The company said interchangeability “raises complex questions that are fundamentally different from those presented by biosimilarity.”

Safety, Competitive Advantage

On Nov. 25, Amgen Inc. announced that it had filed a biologics license application (BLA) for a biosimilar for AbbVie's Humira (adalimumab), noting that it had conducted phase III comparative efficacy and safety studies in both moderate-to-severe plaque psoriasis and moderate-to-severe rheumatoid arthritis.

AbbVie's 2014 global net revenue for Humira was $12.5 billion, more than 60 percent of the company's total net revenue. In its Sept. 30, 2015, third-quarter financial report, the company showed Humira global net revenues for the first nine months running 12 percent ahead of the same period for the previous year. Its key U.S. patent protection for Humira is set to end in December 2016.

In its petition, AbbVie said that Humira is licensed to treat rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, plaque psoriasis, hidradenitis suppurativa, adult and pediatric Crohn’s disease and ulcerative colitis—seven more conditions than those for which Amgen submitted data in its BLA.

A requirement that Amgen prove interchangeability for all of those conditions likely would delay Amgen's ability to achieve an interchangeability designation for its biologic product and presumably give AbbVie a continued competitive advantage.

But what AbbVie stressed in its petition was that the FDA, in assessing interchangeability under the Biologics Price Competition and Innovation Act (BPCIA), should ensure that applicants meet the “Safety Standards for Determining Interchangeability” set forth in Public Health Service Act Section 351(k)(4) for each of the RP's licensed uses, regardless of whether the applicant intends to label its product for every such use.

‘Any Given Patient.'

AbbVie said in its petition that, unlike most small molecule drugs, biologic products are large enough to be recognized by the human immune system, and, in some cases, the system may “attack” the biologic product, producing antibodies in an attempt to protect the body. This response is referred to as immunogenicity, can lead to significant and sometimes fatal side effects in patients, and raises concerns about switching one biologic product for another, AbbVie wrote.

The petition quoted Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, in her statement at a Sept. 17, 2015, hearing of the Senate Committee on Health, Education, Labor and Pensions: “The question is would [continued switching] cause additional harm because of unexpected immune responses. [And] what the concern has been is that this continued switching could raise that immunity—sort of provide a booster effect and cause untoward effects. [The] problem is that the human immune system is capable of detecting tiny variability.”

In its argument, AbbVie cited Section 351(k)(4), which says that for a product to be designated as interchangeable it must be a biosimilar to the RP, be shown that it can be expected to produce the same clinical result as the RP “in any given patient”; and, when it's administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the RP isn't greater than the risk of using the RP without such alternation or switch.

Under the BPCIA, AbbVie wrote, a biologic product can be deemed interchangeable only if it can be expected to produce the same clinical result as the RP in any patient for whom the RP is specified—“meaning any patient covered by any approved reference product condition of use.”

The petition also asked that the FDA clarify that the statutory standard for establishing interchangeability differs in both kind and scope from the standard for establishing biosimilarity.

In addition, AbbVie said, the FDA should convene a hearing under 21 C.F.R. Part 15 to consider the complexities of interchangeability, including the implications of interchangeability decisions in a multi-source product environment where multiple biosimilar biologic products may have been found interchangeable with a single RP but not each other.

Earlier AbbVie, Amgen Petitions

Both AbbVie and Amgen were involved in other biosimilars-related citizen petition activity in 2015.

On March 25, the FDA denied Amgen's petition that the agency require biosimilar applicants to certify they will participate in the information exchanges specified in the BPCIA. 

Those provisions were the subject of Amgen's litigation against Sandoz concerning the first FDA-approved biosimilar under the BPCIA, Sandoz's biosimilar of Amgen's cancer treatment Zarxio.

On June 2, AbbVie filed a citizen petition asking the FDA to require labeling that describes how a biosimilar is different from the reference biologic, including whether it's designated interchangeable, which it supplemented in a Aug. 13 letter.

An Amgen spokeswoman told Bloomberg BNA in a Dec. 30 e-mail that the company didn’t have a comment on the AbbVie petition at this time.

To contact the reporter on this story: John T. Aquino in Washington at

To contact the editor responsible for this story: Randy Kubetin at

The petition is at


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